Vaccines Under the Microscope: How can we know they are safe?

Summary

Highlights

• Dr. Paul Carson explains the comprehensive process to ensure vaccine safety.
• Vaccines undergo detailed phase trials (1, 2, and 3) over 10-15 years. 📅
• Public hesitancy is often about perceived vaccine risks versus disease threats.
• Active and passive surveillance systems continually monitor for safety. 🛡️
• Vaccines have achieved monumental success in drastically reducing diseases.

Key Takeaways

• Vaccine development is a rigorous process spanning 10-15 years, ensuring thorough safety assessments. 🕒
• Even after approval, vaccines are closely monitored for safety through various extensive systems. 🔍
• Public hesitancy towards vaccines often stems from the perception of their risks being higher than those of the diseases they prevent. 🤔
• Vaccine safety systems can detect adverse events, but rare events often need large, continual post-licensure studies. 📊
• Vaccines have significantly reduced or eradicated diseases, which some people now see as less of a threat. 🚫

Overview

Vaccines Under the Microscope: How can we know they are safe? Transcription

• 00:00 - 00:30 thank you for watching the recording of vaccines under the microscope how can we know they are safe this session was presented by Dr Paul Carson on September 19th 20124 to earn continuing medical education also known as CME credit you must complete the preest watch the recorded webinar and complete the post test and evaluation
• 00:30 - 01:00 to access the preest please scan the QR code or follow the link available on the screen for those seeking one maintenance of certification point for the American Board of Pediatrics or for the American Board of internal medicine you must watch the recording and complete the post test and evaluation m points are only available for board certified doctors fellows or residents
• 01:00 - 01:30 details on how to access the post test and evaluation will be available at the end of the recording enduring CME and ml points will be a available for watching this recording until June 30th 20125 good afternoon everyone my name is Dr Trac Newman and I'm the medical
• 01:30 - 02:00 director at NDSU Siri today I have the pleasure of introducing Dr Paul Carson who will be presenting this webinar titled vaccines under the microscope how can we know they are safe Dr Carson is an infectious disease physician with over 25 years of clinical experience he is currently an ameritus professor of practice in the North Dakota State University Department of Public Health where he founded and previously served as the medical director for the center for immuniz research and education he is
• 02:00 - 02:30 also a professor at the University of North Dakota school of medicine and Health Sciences he has held many roles within Stanford including chair of the Department of infectious diseases director of clinical research and chief quality officer Dr Carson welcome you can begin great um good morning or good afternoon everyone depending on where you are maybe good evening I don't know how big our reach is today uh welcome U to everyone I'm happy to be able to be
• 02:30 - 03:00 with you to go over I think what is a really important topic which is is really kind of addressing um a lot of the safety concerns and hesitancy that we're seeing in uh in the general population and a lot of our patients um and I think that really starts with us having confidence in our vaccines and their safety and that I think starts with understanding the process by which we ascertain whether they're safe or not and I'm going to go through that um in
• 03:00 - 03:30 some detail with you today uh here are the um uh disclosures and maintenance of a certification statement um we are supported by a grant from the CDC uh and I have no relevant Financial relationships uh uh to disclose um so the objectives for uh today's presentation if I can get this to advance sticking on me here here we go um it are the are the following uh this is what I kind of hope to accomplish
• 03:30 - 04:00 with you uh first is to recognize how the safety is prioritized in the vaccine development and our approval process second is to identify the differences between vaccine safety surveillance systems in the US and how they collaborate to assess potential safety and then finally I want to go over some historical examples of how vaccine surveillance systems have successfully identified and responded to safety concerns um so let's first just acknowledge uh what an incredible uh
• 04:00 - 04:30 benefit vaccines have been um to the world in the really over the last century when we look at um even in the 1900s here 20th century annual morbidity or or significant illness from um the diseases on the left uh we can see tens to hundreds of thousands of cases of illness from these various uh scourges that were major problems for um uh mostly children but uh all ages um uh in
• 04:30 - 05:00 the last century and we can see in you know as of 2021 uh the U annual incidents of those uh uh cases or numbers of those cases and the dramatic declines uh that have occurred which are almost um almost in the largest part due to the Advent of vaccines small pox gone diptheria essentially gone U measles markedly reduced um moms pressus polio rubella congenital rebell syndrome etc etc most
• 05:00 - 05:30 of these things have uh um over 97 to 99% reductions um with the Advent of vaccines but in there in actually kind of Lies the problem we we've been so successful at eliminating or uh so so markedly reducing these diseases that they faded from our Collective Consciousness and people no longer really perceive these as a significant threat when I talk to some of um you know the elderly members of my family uh
• 05:30 - 06:00 or friends or acquaintances that that they can readily recall some of these diseases from the 1940s 50s and 60s and are sort of shocked that people no longer you know think about these or care about these because they were very real in their families just a few decades ago and so I think accordingly um we've seen uh people perceiving that maybe the risks of the vaccine are greater than the risks of these diseases which for the most part they don't see uh and here
• 06:00 - 06:30 we can see from the Gallup poll that uh the author of this report notes that faith and vaccines have fallen 10% and that was uh January 2020 prior to co uh Co I think substantially contributed to a loss of uh trust in our our traditional Public Health Systems and in vaccine confidence and uh when we look now uh at you know the general population we see that uh somewhere around 50 to 60% of
• 06:30 - 07:00 Americans have some or great concerns about vaccine safety so a substantial portion of the population is contending with this in one way or another and we know that our our patients and our loved ones um often are somewhere on a spectrum of of vaccine acceptance versus hesitancy soing you know the one hand on the one end of this we have um patients and and families that are willing to accept pretty much every anything that doctor the provider recommends uh to the
• 07:00 - 07:30 far other end of the spectrum where they're going to refuse uh all vaccines and and they're they're more likely to tell you what you don't understand about vaccines but the majority of the population is somewhere in this sort of Center where they may be unsure or accepting some delaying and refusing others or more inclined to refuse but aren't certain in their hesitancy whether that's the best thing and that's where we we especially want to uh a aim
• 07:30 - 08:00 our efforts um in in helping people become more confident now the World Health Organization has recognized uh That vaccine hesitancy is is one of the greatest uh Global threats um so even in 2019 again before the co pandemic they had listed on um uh one of their major reports that vaccine hesitancy was one of the top 10 uh greatest threats to Global Health um and I suspect that's only gotten worse in the last few years
• 08:00 - 08:30 years and this is having real world consequences we've seen the outbreaks of things like measles with the Disneyland outbreak that was an old outbreak of measles in Minnesota now a more recent one things like um pressus making comeback polio making a comeback uh you know and here uh um the first polio case not too long ago um being detected in New York State uh almost Unthinkable um you know a decade or so ago uh so the and these are almost um almost
• 08:30 - 09:00 exclusively like for example our recent measles outbreak uh in Minnesota was almost exclusively in unvaccinated um children um so it it really is incoming on us to uh try and help uh overcome this uh hesitancy by um being confident in ourselves that we have a process that uh assures that our vaccines are safe we
• 09:00 - 09:30 we want our vaccines certainly be to be effective and necessary but uh most especially we want to know that they're safe um that's that's in multiple surveys the primary concern for people when it comes to hesitancy so what does safe mean um so what it does not mean is zero risk okay nothing has zero risk taking an aspirin does not have zero risk taking your mot and doesn't have zero Risk Everything has some degree of risk getting in my car and driving my kids to school has some risk
• 09:30 - 10:00 um so we don't mean zero risk but we are trying to weigh the risks and benefits of uh of the vaccine and more importantly of the pathogen uh that um people may be exposed to so that includes what's the incidence or likelihood of acquisition of that pathogen and uh what are the likely uh uh serious outcomes uh from exposure and acquisition of that pathogen compared to uh the safety uh of the vaccine and we'd
• 10:00 - 10:30 like that difference to be at a pretty wide margin because we're giving vaccines to uh for the most part healthy people so let's kind of walk through uh some of the process of uh how how a vaccine comes you know comes to uh approval from the development process up to public availability and what are the processes involved to assuring that they are safe so this really um is housed under the authority of the uh Food and Drug ad Administration the FDA um the FDA must
• 10:30 - 11:00 license a vaccine before it can be used in the US and so the FDA has a number of different requirements for that to happen they uh require that uh the vaccine components have a purity standard that if they go from one lot to the next or one manufacturing plant to the next you're getting the same product um in a in a pure form that does not uh vary significantly um they want to assure that it's potent uh they want to know that it's effective and most importantly they want to know that it's
• 11:00 - 11:30 safe before they're going to license this so what does that process entail um so the traditional uh um process often is a timeline that spans 10 to 15 years and a big chunk of that is in this um exploratory and preclinical phase so this is the you know laboratory tests um and then it Go often goes on to animal tests um and if you can show that you've got a pure product uh that can be
• 11:30 - 12:00 reliably manufactured and it appears to be immunogenic and and hopefully uh protective in animals then the van vaccine manufacturer can file what's called investigation of new drug uh application that's that's uh an application to the FDA to say may we begin human trials if the um FDA is satisfied that the animal data and pre-clinical data and laboratory data is um uh adequate they will grant that license
• 12:00 - 12:30 and then they can start phase one um and maybe phase two and phase three trials so phase one trials are usually in small groups of people um they may be dozens uh um and there and it's looking primarily to see if there's an immune response uh are they getting you know the anticipated immune response um uh sometimes that may be with dose finding as well like what's the best dose and to make sure that they'll also look for any major safety signal signals if that all
• 12:30 - 13:00 looks okay it can move on to phase two which uh is a greater number of people and again is now looking um harder at um uh um imun immunogenic response uh this may be more specific to dose finding to finding the optimal response and a little uh more data on safety signals if that uh all looks okay then they may proceed on to phase three study which are typically thousands to tens of
• 13:00 - 13:30 thousands of subjects where you're now comparing them to a control group so you have a vaccinated population compared to either an unvaccinated or whatever the current um standard of care is and you're comparing these in much larger populations with the intent of looking at both efficacy so you want to see does it actually prevent the disease and Target in that population and most importantly safety are there any major safety signals if that all looks okay
• 13:30 - 14:00 then they can uh file uh um uh a a licensing application the FDA will then look look at usually it's thousands of pages of documentation that are required um that can take months to review and if that uh All Passes muster they'll Grant uh that license and then the um manufacturer can start making the vaccine and um Distributing that for administration of the population um so those are the various steps along
• 14:00 - 14:30 the way um here's just another pictogram of that um and kind of layer on top of that is when you look at potential new vaccines making the way through the pipeline a whole lot of them never even get approved for those phase one two or three studies of those that do and and make their way through the process you may have um dozens of vaccine candidates with only maybe one uh making it uh through to uh lure and on average only
• 14:30 - 15:00 about 10 to 12% of all vaccine candidates make it uh to that stage then um to to just kind of put a Finishing Touch on this the FDA along with the CDC then do continued um uh monitoring for safety signals even after uh lure these are the post approval monitoring and research activities and we're going to go into some details about uh these as well um here's a few of the different uh uh
• 15:00 - 15:30 vaccines and their phase three trials that were required for lur so you can kind of see that um in those phase three trials this is the total number of study subjects and they're you know on the lowest end here uh at the top is the Roto Shield uh the original rotavirus vaccine we're going to talk more about that as a case example in a minute uh with only 4,400 total subjects but most of them in the tens of thousands of of subjects uh studied these are uh I
• 15:30 - 16:00 participated in these as a um um a researcher for some of these vaccine trials very rigorous lots of paperwork uh very very detailed very difficult to do um very expensive take a long time uh and um uh meet have to meet a very very high bar so what are some of the strengths and weaknesses of these uh uh of this initial process so the strengths are
• 16:00 - 16:30 this is a stepwise safety and efficacy assessment they are rigorous these are the best uh type of a study uh as far as um eliminating bias and finding true effects um R phase three randomized Placebo control trials usually blinded um so they're they're good at decreasing bias they're better at assuring group equivalence that you're kind of comparing Apples to Apples they're better at getting the actual vaccine effects both efficacy and risks and
• 16:30 - 17:00 they're typically powered to detect efficacy and common Adverse Events um the limitations are that um they can't detect very rare Adverse Events when you you've got thousands to maybe tens of thousands of study subjects you're not going to detect um an adverse event that's maybe in the you know one out of a 100,000 uh people nor can they detect very late or delayed Adverse Events they're expensive and they're difficult
• 17:00 - 17:30 to do they take a very long time and often pediatric populations and Pregnant uh women are often studied at a much later date now let's kind of focus on two that I think are of the most common concerns expressed by um patients or the general population that is that is you know are we detecting every uh adverse event or even rare ones and are we detecting very late or delayed Adverse Events let me first address the second one here
• 17:30 - 18:00 delayed side effects I'll put out a statement here and I've I've yet to have this um uh proven wrong and and uh experts in vaccine safety and and trial process will say this as well that in the history of all vaccines licensed in the United States no serious adverse ofer side effect has been found after six to eight weeks after the vaccine's been given now um uh that makes some sense when you think about how vaccines the vast majority of the time uh lead to
• 18:00 - 18:30 a potential side effect um it it's usually either a direct Toxic effect from the vaccine components itself and that's usually going to appear in the first few days or maybe a couple weeks after the vaccine is given when the amounts of the vaccine ingredients are still highest in the body um or uh it may be due to uh the immune response solicited by the vaccine and that immune response causing some UNT effect that you don't want and the immune um
• 18:30 - 19:00 response typically Peaks somewhere around four to 6 weeks so we would expect those type of side effects uh to appear most often in that uh window of uh one to two months there is a rare exception of this that I can talk about in The Question Answer period uh later that wasn't in any us licensed vaccine but it's something called um uh um anti antibody dependent enhancement it's a a rare immunologic problem that can that
• 19:00 - 19:30 um has affected the Denay vaccine not licensed in the US um and can and can be delayed um you know I I think it's kind of worth uh thinking about like how good are we at detecting uh you know uh Adverse Events I'm going to get you know if you want to nerd out a little bit here a little bit stick with me on this slide if if this sort of thing bores you just glaze over for a second here before we get on to the next thing so um a a quick little cheat statistical cheat or
• 19:30 - 20:00 rule of thumb that you can use is something called the rule of three and we can it's a statistical uh um observation that is a shortcut to more sophisticated statistical testing and the rule of three uh states that you can be 95% confident that your sample size or n can detect events at a rate of 3 over n or greater so kind of giving an example of that let's take the uh um phase three trial
• 20:00 - 20:30 for the fiser uh mRNA covid vaccine um that trial had 44,000 participants so 22,000 in the vaccine arm 22,000 in the uh Placebo arm so if we use the rule of three we can say we can be 95% confident that we should be able to take three over 22,000 participants in that Tri the vaccine arm for a percentage of 013 or we should be able to find events that are as common
• 20:30 - 21:00 or more common than one out of 7300 roughly so that's pretty good you know that that would be a pretty rare event um but it's not we're not going to detect something that happens one out of 10,000 uh shots um and we'd like to know that right we'd like to know even rarer than that but um uh but from this we can say we we can be 95% confident that we should be able to detect serious Adverse Events or occurring in a rate of 3 over
• 21:00 - 21:30 n which in this case comes out to greater than or equal to one out of about 7300 if you want to know if it's statistically different than the background rate of that problem then you got to compare that same rate in the placebo arm so just kind of hold this in your mind this this rule of three when we kind of think about some future um case examples here um and you know vaccines can cause serious uh Adverse Events these are some of the recognized known um serious Adverse Events from some vaccines so all vaccines roughly have an anaphylaxis
• 21:30 - 22:00 rate of about one out of a million our our phase three trials aren't going to detect that and in the case of the covid vaccine it was a little more common than that it was uh closer to maybe four out of a million um but the the the trials didn't find that we had to find that in post marketing surveillance systems which we're going to talk a lot more about in a second um influenza known to cause gon bra syndrome um maybe one to at the highest 10 per million which is actually subst Al lower than uh gon
• 22:00 - 22:30 syndrome caused by influenza itself uh but it is a known potential complication measles MST rebella can cause idiopathic thropic perpa and about one out of 40,000 MMR vaccine can cause fbal seizures particularly in young children in uh rates out of one out of 2500 or one out of 1250 with the mmrv um the Rota Shield uh uh original Rota virus vaccine led to interception uh you know telescoping of the bowel
• 22:30 - 23:00 with intestinal blockage in about one out of 11,000 infants and the subsequent versions of the RO virus vaccine um like the rotch uh dropped that down to about one out of 100,000 we're going to use that a little later as a case example on how different systems work all right so now let's move to the postlicensure vacine safety monitoring systems in the US um first you know uh for our CME purposes a question for you to ponder we
• 23:00 - 23:30 don't have an audience participation participation system U built in right now but just kind of think about this I'm not going to give you the answer I want you to think about this question and see if you can answer it after we go through the next few slides so which of the following best describes the key difference between the vaccine adverse event reporting system or vs and vaccine safety data link another uh major system uh employed for our uh vaccine safety surveillance a both systems rely on active data
• 23:30 - 24:00 collection B vs is a passive reporting system while vaccine safety data link actively monitors Healthcare data C vaccine safety data link um focuses only on childhood vaccines while vs covers all ages or d vs is the only system that can establish causality between vaccines and Adverse Events so think about that see if you can answer that now see if you can answer it here in a in a few more minutes so let's look at these various
• 24:00 - 24:30 systems that uh we use in the United States uh to better assure uh vaccine uh safety um so uh first we're kind of start with the sort of centerpiece here which is the vaccine adverse event reporting system hopefully all of you who are providers uh uh or pharmacists are well familiar with this because we are actually required by law to report serious adverse any serious ad event we suspect following a vaccination in our
• 24:30 - 25:00 uh patients um and and serious Adverse Events means either death or hospitalization but we can we can report any uh concern after vaccine into vers and it's not just providers anyone uh can um report into this um including uh patients or anyone from the general population so this is used by the FDA and the CDC to collect reports of Adverse Events that happen after a vaccine it is a passive Reporting System meaning
• 25:00 - 25:30 it meaning it relies on individuals and healthare providers to send in reports of adverse health events now again we are required do we always do that not always but we really really should be making strong efforts to do that scientists monitor this uh system and the reports to identify Adverse Events that need to be studied further uh emphasis on there it doesn't end there um these these reports of Adverse Events are Then followed up on
• 25:30 - 26:00 with additional research um unexpected events or things that happen to appear more often than expected we are trying to find patterns in in the you know all all the kinds of reports that uh come in there we're looking for a signal it is it is essentially an early warning system and what V is trying to do is cast a very wide net um uh to to fish out any potential signals that might be out
• 26:00 - 26:30 there uh the strengths of this is that it's a wide net anyone can submit a report to vs and it can serve as an early warning hypothesis generating system uh but it has some major limitations it is passive meaning it's not going to capture all Adverse Events it and it doesn't have a true denominator we if an event comes in with you know uh some serious uh uh um adverse event that appears to be you
• 26:30 - 27:00 know more than we might expect we we don't have a denominator that how many people got vaccinated you know what what's the percentage we can't we can't say that from Vees most importantly there is no control group to compare rates in vaccinated versus unvaccinated populations so you cannot determine causality big emphasis here it can only raise questions and often especially when it comes from uh you know the general population these reports May lack details or contain errors um so you
• 27:00 - 27:30 don't you don't know that you're getting really uh um accurate information um and this is a problem because uh um this database which is also publicly available anybody can look at the results out of this um the CDC tries to be very transparent uh with this process and as such makes this data available to the general population and you can see all kinds of people uh who not know how to mine this data very uh
• 27:30 - 28:00 carefully um drawing all kinds of uh conclusions that they really shouldn't be out of there and and it's been used to actually support or fuel anti-vaccination sentiment um you know here's an example uh here here's this woman holding up a sign uh this is during covid you know saying vax deaths you know UK 1,470 US 11,000 EU 18,000 you know presumably she's uh um talking about um all our ve system and similar systems in uh Europe
• 28:00 - 28:30 where deaths were reported after the covid vaccine um and here she puts a little question mark you know maybe times 10 uh because not everything gets reported in there right um it's a passive surveillance system well um this uh uh gets to uh um what we we as human beings want to do naturally our brains are really hard wir to make causal inferences and I I give
• 28:30 - 29:00 as example here some of you may recognize uh Jenny McCarthy um you know she was in some kind of be movies and uh was a talk show host for a while and for a while her Paramore was the actor James KY um she has a son uh named Dylan who she's been very public about um who developed some pretty significant um developmental disability learning disability and uh her statement is that you know know he was vaccinated and
• 29:00 - 29:30 something changed and she's she's I she's said it on other venues I don't care about all your studies I don't cover out your science my son is my science and I'll ask my students you know is she unreasonable here you know she saw her boy growing up seemingly healthy normal and then something changed and she was able to sort of link that happening I don't know if it was days or weeks or months after a vaccine but she thought that it followed a vaccine and you know was trying to make some connection like why did he change
• 29:30 - 30:00 what happened to my son and and I would say that's not an unreasonable thing our brains are hardwired to look for reasons why bad things happen um that's maybe captured a bit more and something that I heard a lot during the pandemic um you know we'd hear somebody going into the vers database saying something like this I've heard that over 18,000 people have died from the covid-19 vaccine is this true um well no that's not true um but it it
• 30:00 - 30:30 gets at something that uh is sort of a Hal truth um first of all it's more like 9,000 people a lot of people who were um mining the data in the um in the vs database didn't know that you have to put certain filters on so that you don't get duplicates sometimes reports have duplicates if um if if they're reported in certain ways and that's a common error and when you pull data so oftentimes the numbers were doubled uh
• 30:30 - 31:00 from what they actually were and and there's a a real issue with the term from versus after the vaccine so it's true that there were uh few a couple years back about 9,000 reported deaths after a covid vaccine um so what does that mean uh from versus after it's it's actually a very big difference um so this gets to uh what's called the post Hawk fallacy which you know is post Hawk
• 31:00 - 31:30 Ergo proter Hawk meaning after it therefore because of it um and that's a logical error um there may be a correlation but as we often like to say you know correlation does not equal causation uh here the kind of you know classic example is the rooster crows the sun comes up the rooster crows the sun comes up the rooster crows the sun comes up um is tight tight correlation with the rooster crowing before the sun comes up did the rooster cause the sun to to come up no there's a strong correlation
• 31:30 - 32:00 but we know that's not causal a better example and more to the point was in Dr Paul off at Dr offit a pediatric infectious disease specialist and a vaccine expert and he wrote in his book deadly choices uh about a an example of a um I believe it was a friend or a colleague um at another Health Care System who was a physician who had uh brought his son uh somewhere I think around the age of 68 months um to I believe it was a flu Clinic
• 32:00 - 32:30 where they have you know like the standing line they have a flu Blitz and you can kind of get get your kid vaccinated uh um you know on the spot without having to make an appointment and it was um and this uh dad you know stood in line for uh quite some time was it was after work it was getting close to dinner time he decided I'm waiting too long I'm going to do this another day and he went home uh without uh completing uh the vaccine um and very tragically and very sadly his son died
• 32:30 - 33:00 that night presumably from SIDS or sudden infant death syndrome and and this uh dad uh medical provider you know came to the realization you know in the wake of that tragedy had he gone through that line and had he gotten um his son vaccinated it would have been very difficult for him not to have blamed that on the vaccine that his healthy boy was fine he goes to through the line gets the vaccine and dies that uh night tragically um
• 33:00 - 33:30 what else could it be right but he would have been 100% wrong because his son died um tragically uh serendipitously from um from SIDS and it would have just been um uh just by circumstance that it might have been might have been in association with vaccine it would have been an erroneous conclusion to put a finer point on that if we look at any given day in America any day in America we have about 540
• 33:30 - 34:00 people developing the new onset of a seizure we've got about 2200 people that will have a heart attack about 2 200 people that'll have a blood clot like a DBT another 2200 people having uh a stroke and about 8,000 people will die on any given day in America um that is uh every 160 seconds somebody with a new seizure every 39 seconds a new heart attack 35 seconds a new blood clot every 39 seconds a new stroke and every 11 seconds someone will
• 34:00 - 34:30 die in America now think about that with um the covid vaccine as an example uh where we had you know a massive vaccination effort and in the span of just a few months we vaccinated almost uh two-thirds of the population uh 260 million people by June of 2022 and most of those by September 21 so layer on top uh you know of this Mass vaccination effort the fact fact that on any given day we're going to have all these bad
• 34:30 - 35:00 things happen to someone every 160 seconds 39 seconds 35 seconds 11 seconds every 11 seconds somebody dying of course somebody's going to just die or have a stroke or have a heart attack or a blood clot or a new seizure just by happen stance um an hour a day a week a month after getting a vaccine um so uh we have to be able to pull out that signal from the noise and
• 35:00 - 35:30 let's look at the deaths for example and here I'm picking on um you know the covid vaccine since it was so fresh in our minds uh on a lot of the safety issues here's the here's the deaths reported into uh vs and age distribution and it's it's predominantly uh the elderly um as you might expect um old people were a main target for the vaccine campaign and old people die of heart attacks and strokes and you know uh and are frequently make up one of those
• 35:30 - 36:00 8,000 uh people or in fact the majority of those 8,000 people who die on any given day and so it's sort of as we might expect in Bears so we have to have some way of pulling out a a true signal of what really is from the vaccine from the background noise of bad things happening to people every day and to do that you got to compare a vaccinated group to a control group of some kind preferably in unvaccinated uh group um you can't assign causality
• 36:00 - 36:30 without doing that so all these people you know that will say you know this bad thing happened to my aunt Susie after a vaccine I shrug my shoulders and go wow you know I'm sorry to hear that I hope your provider uh put a report into vs but we can't really say whether it was a vaccine or not without more information and that means looking at populations of of vaccinated people versus a control group now vs our our
• 36:30 - 37:00 big Cog wheel in the middle can't do that we need other systems to do that and um and for that we preferably want to look at active surveillance systems so things that are trying to find uh signals um not just passively waiting for reports uh so as I've mentioned passive surveillance are unsolicited reports of Adverse Events um sent to a central database that's mainly theirs active surveillance is proactive assessment we've got a variety of large
• 37:00 - 37:30 databases to do this we often have captive populations so you can get a truer denominator so you can get a real rate um and these data are often used to verify signals from vars so it doesn't stop with vars vers generates a question and then we investigate that question with better more robust data we do this with vaccine safety data link and a uh prism best and vsafe which I'll mention all here in a second first is the vaccine safety data link if you take nothing else away from this talk I hope
• 37:30 - 38:00 you will remember this system because it's a really good really important system in our uh vaccine safety armamentarium vaccine safety data link um links uh a number of uh large integrated healthc Care organizations in the United States nine in total um that have robust electronic medical records and they pull data uh and these nine organizations which is Kaiser out west Health Partners in Minnesota Marshfield
• 38:00 - 38:30 Clinic in um Wisconsin the Harvard Pilgrim system out in Massachusetts and the CDC Emory uh system in Atlanta um these nine organizations cover over 12 million persons um that we can dig deep into their medical records and and these these um patients are frequently uh you know captive in those systems so we can use those systems to have a control group so what kind of study do we we get out of these um this is kind of what I
• 38:30 - 39:00 call the hierarchy of evidence in the type of studies you know evidence quality and causality gets better and better as we move up this pyramid and it's um uh pretty low or poor at assigning causality the lower on the pillar pyramid so when we have a case like Jenny McCarthy saying something bad happened to my son that's tragic that's noteworthy but it does not get us uh um uh anywhere near kind of saying that was causal um randomized controlled trials
• 39:00 - 39:30 are and metaanalyses of randomized control trials are the best but as I talked about they're usually limited to the thousands to tens of thousands they're expensive they're hard to do they take a long time um and and you're not going to get those very rare Adverse Events so uh we can focus on these types of studies prospective cohort studies retrospective cohort studies and case control studies I won't go into this epidem ologic study design uh too deeply but these are very good what we call
• 39:30 - 40:00 epidemiologic studies or observational studies where we can get closer to that question of causality especially with the prospective cohort studies and those can be done through these linked um uh Health Systems electronic medical records and other types of systems where we can look at claims data like Insurance data so here's an example of one of the reports here this was published in jamama again using the covid vaccine is an example so this is after the covid vaccine was released
• 40:00 - 40:30 without being used in circulation number of questions came up about its safety so uh vaccine CDC said to vaccine safety data link look you know we need to look into these these concerns people are raising and questions people are raising and so they said let's look at these this list I think it's about 25 it's kind of fine print here but you can kind of squint and look at that these 25 bad things that people are wondering about providers are wondering about or maybe maybe in A's safety signal you know 25 bad things let's take a look uh
• 40:30 - 41:00 at these in a vaccinated population um compared to to a control group and they did that in almost 12 million doses of mRNA and 6.2 million individuals so a huge number of uh in the study population and they found no increased risk of any of these conditions except myocarditis in the 12 to 29 year old age group particular males where there was about a 3.7 fold increase risk and rare
• 41:00 - 41:30 anaphylaxis about 5 to8 per million which was higher than other vaccines that are typically at about one out of a million so there were a couple of safety signals um uh that uh that uh were uh proven out of that and a whole lot that did not bear out um there are other uh safety systems that that also do active surveillance uh and a couple of those with potential control groups so um be safe uh you may
• 41:30 - 42:00 have participated in this if if you got a covid vaccine you invited to um participate in active surveillance on what happened to you after you got your vaccine and you get these text based uh reminders um it was a smartphone based monitoring program for covid-19 uh launched in December 2020 there was over 10 million V participants so again big number um completing more than 151 million Health surveys about their EXP experiences following the covid vaccine uh vsafe data uh have been
• 42:00 - 42:30 included in more than 20 scientific Publications and a newer version of this launched uh I said was going to launch I had this slide from uh last year but so this is out now um in uh late last year allowed users to share their postvaccination experience with with new vaccines other vaccines other than Co strengths to this are that anyone can enroll in vsafe it's another way to quickly validate safety data from clinical trials or identify safety issues regular reminders to complete a
• 42:30 - 43:00 survey so like you know hey we want to hear from you CDC can follow with participants and submit vs reports as needed um limitations are that it may not properly represent the postvaccination experiences of the entire population meaning that you know people with smartphones who are willing to do this might not be exactly the same as you know everybody else out there um and that might be a you know slightly healthier or less healthy or anxious or less anxious or more health conscious or
• 43:00 - 43:30 less health healthc conscious you know population might not be uh truly representative but uh gets gets a a lot of uh um uh data prism is is called the post-licensure rapid immunization safety monitoring system uh this is actually our largest vaccine safety surveillance system in the US access to information for over 190 million people this uses insurance claims data um to look at and evaluate possible safety issues so it's
• 43:30 - 44:00 not quite as deep a dive as going into the actual electronic medical record but it does get it at a at a nice uh kind of surface level um something that might be serious enough to have generated a health claim or an insurance claim uh so you can get a again large pool to draw from for safety signals strengths are this large size um uh uses this big database of health insurance claims itations is that it can lag in time for accessing the prism data
• 44:00 - 44:30 Medicare population is not as well represented in prism so might not be getting you the best data for the elderly um and it may not be representative of those without insurance coverage so it's it's not completely representative last is uh the best initiative also called the biologics effectiveness and safety initiative uh this is again another active system managed by the FDA it's a compliment to vaccine safety data link and be safe for conducting surveillance of Adverse
• 44:30 - 45:00 Events following vaccination it includes large scale claims data and electronic uh health records and linked claims um EHR so um a little bit more robust uh it can allow us the use of a control group and it's near realtime analysis with the data limitations again May that may not be representative of those without insurance coverage and it can't determine if an association between an adverse and a vaccinations is definitively causal although it it it
• 45:00 - 45:30 helps so here's kind of these uh listed all together that you can kind of look at um with their different patient populations and their different sizes so it's not just vs that we use we've got multiple systems um and I didn't even discuss you know all these there's a couple others with the Department of Defense and and some other uh initiatives as well that you see at the bottom um we also have uh something called the clinical immunization safety assessment project or cisa this is an
• 45:30 - 46:00 interesting uh um Branch uh of our vaccine safety uh and Regulatory process this is a national network of vaccine safety experts from the CDC uh and seven medical centers and some other partners that can be called upon to investigate safety signals or weird things that somebody may have observed uh this project addresses vaccine safety issues it conducts high quality research and assesses complex clinical adverse events following vaccination through active
• 46:00 - 46:30 surveillance um so it's kind of like a swap team that can be brought in to uh do a deeper dive on uh some safety signal um strengths here uh Services vaccine safety uh resource for our us Healthcare Providers assists the CDC and its Partners in evaluating emergeny vaccine safety issues they can Implement prospective multi-site clinical studies with hundreds of subjects so they can say look we want to study this further let's let's set up this uh quick quick study to look into this um they can look
• 46:30 - 47:00 at safety and subpopulations for example uh you know we found that the safety signal for myocarditis and the covid vaccine was really young males it didn't it didn't come out in the general population but it did come up you know looking at in in subpopulations they can receive detailed clinical data on patients and collect biological samples from patients limitations are that it's often a small sample size limits its ability to study rare Adverse Events and clinical trials can be labor and res intensive and it can be challenging to recruit and retain
• 47:00 - 47:30 subjects that's kind of the bane of all research all right and then I I think a really important but often not recognized uh um additional uh very valuable source of vaccine safety information comes from uh data from other countries um and you know where we have vaccine safety data link that covers uh around 12 million population nine Health Systems a lot of other countries have a nationalized health plan so they've got data from everyone
• 47:30 - 48:00 in their in their country um so they can get very uh robust data and we saw for example in Co lots of data coming out of cutter of all places really high quality data you know couple Publications in Jam the New England Journal of Medicine um the UK has a nationalized health plan so they have uh almost their entire country and really high quality data was coming out of there uh on uh from from their UK Health security agents Agency on a weekly basis uh um with some of their
• 48:00 - 48:30 surveillance um uh that they were able to do um Denmark has an excellent uh surveillance system Israel excellent surveillance system South Africa H has a very robust uh surveillance system where we had some really great Publications coming out on vaccine uh safety um through the covid pandemic I'll give you one example of one of these Publications this one was out of Israel kind of similar to one I showed earlier uh out
• 48:30 - 49:00 of the US from vaccine safety data link this was out of Israel which and this was a study on almost the entire population again looking at um a host of different safety concerns about the covid vaccine about again about 25 different bad things that people wondered about maybe being caused by a covid vaccine and they said you know let's look at these in our large database vaccinated population but Let's do let's take that one step further look at these same conditions in our population for people who got covid
• 49:00 - 49:30 versus those who didn't get covid and this was earlier in the pandemic when you could split those out more easily so the blue is looking at risk differences in vaccinated versus unvaccinated and the kind of orange here is looking at the risk differences in people who got covid versus didn't get covid and in the vaccine uh group they had almost 900,000 people in each arm almost 900,000 vaccinated compared to not vaccin inated and in the covid uh Branch they had
• 49:30 - 50:00 about 173,000 um in each group those who got Co 173,000 who didn't get Co and they said all right let's look at what we found so first off um they found that certain things were lower in the vaccinated group um there was less kidney acute kidney injury there was less arrhythmias and less intracranial hemorrhages don't know exactly why that is but um those were lower statistically significantly lower uh and and these numbers represent the the number of cases per 100,000 vaccines so minus five
• 50:00 - 50:30 minus 6 minus three um per 100,000 um uh they did find some things that were higher they found a higher incidence of shingles uh they found a higher incidence of swollen lymph nodes particularly in the axela which we know is a side effect of the vaccine you can get swollen glands there and the myocarditis about three cases per 100,000 um uh overall higher if you looked at the subpopulation of young males um so they did detect some signals there
• 50:30 - 51:00 but compare that to the SARS K2 infected versus the non-infected I mean massively more serious problems acute kidney injury arhythmia deep vein thrombosis intracranial hemorrhage myocardial infarction myocarditis was higher pericarditis pulmonary embolism um again we're weighing the safety of the vaccine versus the safety uh or risks of the pathogen and here when they did this sort of Apples to Apples comparison uh the the the risks from the virus were
• 51:00 - 51:30 markedly worse than the risks of the vaccine so another question for you to ponder uh to kind of consider as we uh progress through the rest of the uh talk which vaccine was suspended after safety surveillance detected a rare but serious adverse event related to intestinal blockage in infants measles mump rebella Rota virus influenza or Hepatitis B if you're paying attention earlier in my talk probably should get this pretty pretty easily um but hold on to that
• 51:30 - 52:00 thought so um let's now look at how these systems work together uh to find and manage potential safety issues using the Rota virus disease and vaccine as an example all right this was uh the face of Rota virus uh very sadly uh you know in the prevaccine ERA this is you know typically an infant or a very young child presenting with diarrhea vomiting dehydration which could um sometimes lead to vascular collapse and death in
• 52:00 - 52:30 the prevaccine era we had about three million cases of this per year in the United States about 410,000 physician visits about a quarter of a million ER visits and about 70 to 100,000 hospitalizations and about 20 to 60 deaths from aoda virus every year uh in the prevaccine era now uh the first candid vaccine uh which was a live oral vaccine was developed um Roa Shield uh vaccine the
• 52:30 - 53:00 FDA approved this with the phase three trial being one on the small side only 4,400 study subjects total that was approved in August of 1998 theirs identified 15 cases of inception so only 15 cases um it didn't have to find all the cases of inception it just had to find enough to generate a safety signal and it did that and the
• 53:00 - 53:30 CDC actually suspended the use of the vaccine in July of 1999 and said we need to investigate this further is this real so the CDC used cisa that sort of SWAT team to go in and investigate these cases they asked vaccine safety data link to do uh um some more intensive uh case series analysis analysis case control study and a retrospective cohort study from those they confirmed there was an association of
• 53:30 - 54:00 inception with uh um uh a prevalence of about one out of 11,000 children developing this Inception and based on that they withdrew the vaccine from the market in October of 1999 um so these safety systems found a signal studied it further found causality uh or high likelihood of caus cality and they withdrew it from the market well you might understand why a
• 54:00 - 54:30 parent might be hesitant to take that vaccine or any of the ones that came after it um but again no vaccine has zero safety issues we are comparing the pathogen to the vaccine and you could make an argument and some have made an argument that the CDC shouldn't have stopped the vaccine and withdrawn it from the market uh based on that data um so going back to that finding events using our rule of three uh being 95%
• 54:30 - 55:00 confident that our sample size can detect events at a rate of three of n or greater and the original R Rota Shield example the cumulative incidence so as a background rate the cumulative incidents of Rota virus hospitalization so serious illness for children up going up to five years of age was one out of 160 kids was going to get pretty sick from Roda virus if they made it to the age of five one out of6 that phase three trial PR small only
• 55:00 - 55:30 4,400 study subjects only 2200 in the vaccine arm using our rule of three 3 over 2200 should have been able to find problems occurring at a frequency of .36% or one out of 733 or greater so that wasn't enough to detect that rare uh problem of one out of 11,000 risk of inception found later but take note that it was still much better even if there would have been something as frequent as one out of
• 55:30 - 56:00 700 um that That vaccine would have been better than that one out of 160 risk from the virus and some people have argued that they shouldn't have withdrawn the virus from the I'm sorry the vaccine from the market based on that and and it led to the discontinuation of this in multiple other developing countries that had worse rates of hospitalization and death than us and it's estimated that that many thousands of deaths may have occurred unnecessarily with the withdrawal of That vaccine from the market uh be that so the pathogen one
• 56:00 - 56:30 out of 160 the vaccine should have been able to detect things more common than one out of 733 probably not an unreasonable thing to have brought to Market um but and it turned but it turned out there was a problem in one out of 11,000 but that did lead uh vaccine manufacturers to study this further and develop newer candidate vaccines aimed at um diminishing that risk of inception so here's the New England Journal uh
• 56:30 - 57:00 study of uh the pentavalent human Bine reassortment R virus vaccine the the follow-up uh vaccine and here you know took years later almost almost seven years later uh to get a vaccine so we went seven years without anything um and here it was like 68,000 study subjects so the CD uh the FDA required a much higher bar for safety um with the subsequent vaccine so we had 68,000 study subjects uh with the mono uh um with the pen aent
• 57:00 - 57:30 vaccine uh the other monovalent rotorx 880,000 study subjects they did not find any additional risk in in this large uh phase three randomized control trial that wasn't enough CDC said you've got to keep studying this uh further with our vaccine safety data link so they initiated a prospective cohort study through vaccine safety data link involving a half a million first Doses
• 57:30 - 58:00 and 1.27 million second doses of the rv5 vaccine and lo and behold they found another safety signal uh really really rare about an additional one and a half into deceptions per 100,000 first dose recipients but that risk was considered uh low enough uh that this was uh worth using this vaccine since uh the the incident of serious adverse effects from actual rotor virus was so High um if
• 58:00 - 58:30 there's any questions please put them in the chat um and we'll try and get those to the end here um and we're coming up on the end uh so benefits and risk summary of estimates of the one Rota virus vaccinate um vaccinated birth um um Birth Cohort to age5 annual outcomes in The Birth Cohort hospitalization ER visit death you know caused by vaccination about 45
• 58:30 - 59:00 hospitalizations 13 uh ER visits maybe up to 02 deaths um uh in in a in in a birth cor uh a typical Birth Cohort in the United States compare that with the numbers prevented by That vaccine 53,000 hospitalizations 100 almost 170,000 ER visits and 14 deaths that's a um uh benefit to risk ratio of uh or prevented
• 59:00 - 59:30 rotavirus outcome per excess interception outcome of over a th000 to one 12,000 to1 71 to1 uh way way worth it finishing up here let me let me give you a few other examples of uh of uh uh signals that have been assessed uh vaccine Associated paralytic polio was identified with the oral polio vaccine a live polio vaccine that we were using in the United States up until a few decades ago this was detected in Vees and it was
• 59:30 - 60:00 further studied in vaccine safety data link data from other countries and a few other systems and then an Institute of medicine review looked into all this data and said yes there's an association of the VAC the oral polio vaccine reverting to a more wild type and being able to cause polio and was an action taken yes they transitioned from the oral polio vaccination to the inactivated polio vaccine in United States so this was this was Finding you
• 60:00 - 60:30 know this was after years of uh uh of surveillance since the initiation of the polio vaccine in the 1950s um DVT from uh the human papala SP vaccine there was a signal that came up in vs and in vaccine safety data link that it might be that women were getting deep vein thrombosis from the HPV vaccine um so efforts were made to study this uh in larger studies in vaccine safety data link Denmark Sweden and
• 60:30 - 61:00 Canada also initiated cohort studies and in those larger studies and studies from other countries no association was found no additional action was taken Johnson and Johnson uh covid uh 19 vaccine and the association of um vaccine induced um uh thrombocytopenic thrombosis um so this was this rare form of blood clot sometimes forming in the in the brain very serious uh potential
• 61:00 - 61:30 side effect this was identified in Vees and in data from Europe um and uh uh additional data came out of Europe with follow-up cesa looked into this uh thought there was a causal link vaccine safety data link and VA data were all employed and an association was found and the vaccine uh use was eventually limited and the FDA eventually rescinded the emergency use authorization of that vac vaccine in the United States M covid-19 vaccines in
• 61:30 - 62:00 myocarditis or pericarditis initially came out from signals out of Israel and it was verified in our vers database uh further studied in uh vsafe cisa vaccine safety data link military systems boret which I didn't talk about Department of Defense data and data from other countries and Association was found uh particularly in young males um there was no change in the vaccine schedules but we did uh put into effect an optional 8we interval between the first and
• 62:00 - 62:30 second dose particularly in uh young people are or uh and especially young males that was added to the recommendation so a partial change and and that extending that interval was uh associated with a much lower incidence of myocarditis few others here finishing up uh and I I point these out because this is a different different sort of reason for assessment the use of marasol or the Mercury preservative was became a concern in um you know is causing autism
• 62:30 - 63:00 no signal was ever found for this it was just public concern they looked into this in V vaccine safety data links cisa The Institute of medicine issued a report on this we looked at data from other countries no association was found but because of the ongoing drum beat of you know fears about this actually therasol was removed from all childhood vaccines some people said that was a mistake sort of caving into unwarranted fears hard to know what's the right thing to do there um again public
• 63:00 - 63:30 concern about the HPV vaccine causing um primary uh ovarian insufficiency or form of um infertility looked into again ve cisa vaccine sa link no association found no change was made to this vaccine fizer's balent co9 vaccine and possible stroke in 65 year olds this was a signal that came out of post marketing surveillance in vaccine safety data link looked into
• 63:30 - 64:00 further inve CMS and VA data best data and data from other countries was not validated in better higher quality and larger studies no changes made and more recently uh there's been some question of aluminum adant in vaccine possibly being associated with asthma again this kind of came out of public concern was looked at in vaccine sa sa vaccine safety data link and data from other countri and there's a maybe here so vaccine safety data link found a kind of a weak
• 64:00 - 64:30 Association data from other countries has not confirmed that Association um some action is being taken uh majority of the data doesn't support the association but this is um now getting investment with bigger better uh higher quality studies from these various databases so I'll just finish with a quote from uh marce hman one of the one of the developers of many of our current childhood vaccines he was brilliant vaccine researcher and you know he said I never breathe a sigh of relief until
• 64:30 - 65:00 the first three million doses are out there and this does acknowledge that we can't find every rare event in in the initial FDA approval process we rely on these uh postlicensure surveillance systems to find those very very rare events um which hopefully are always rarer than the risk of the pathogen itself so I hope that can help some of you in your confidence about our vaccine safety and Regulatory process I'm touch over time here but I'm happy uh to take questions if there are some in the chat so the
• 65:00 - 65:30 first question I see um is is there an effort to ensure that persons with disabilities are included in phase three trials um this I think gets to like even a bigger question about minorities and and other subpopulations and I I guess I would have to say the answer to that is partially um there there's a greater and greater awareness that we need to do a better job of getting um truly represented populations um into our our trial data
• 65:30 - 66:00 um but as as was pointed out by some critics for example the myocarditis uh issue with that wasn't picked up in the original kind of safety deal it was really a subpopulation of young males and so you have to sometimes dive into the post-licensure data um there I did see for example in the co trials much greater effort to try and get in minority populations to be better represented as to the question about dis disability patients uh with persons with disabilities in particular um I'm not
• 66:00 - 66:30 you know I would say the answer to that is probably no with a caveat and that is that um the vaccine manufacturers and and the trials are typically aimed at the groups that are considered to be at risk so um for example the RSV vaccine uh for adults that just came out really you know emphasized looking at um the elderly and included in those people with uh chronic medical conditions because we know those are that's
• 66:30 - 67:00 population at greater risk for severe outcomes from RSV so it it may Target populations that may be at the highest risk um but uh I I would say to be fair uh that you know subpopulations like maybe some particular disabilities uh might have to come out in in those um larger uh cohort studies done in post marketing surveillance second question was does the FDA ever agree to use or authorize foreign vaccines such as the
• 67:00 - 67:30 ones Europe can produce when fighting the same disease no uh we do not accept any other country's uh process or regulatory process if they've approved it that doesn't we will not approve it it has to go through our own FDA uh trial and approval process um they may look at that data and say this looks like a worthy candidate vaccine and do the trials uh in the US but um uh I I don't think you can uh there there the V fact I'm certain vaccines cannot
• 67:30 - 68:00 be approved based on another country's uh data um I do see there's a hand raised I don't know if that's a another question or something but um um questions for now thank you for answering those thank you again for joining us today and we look forward to seeing you again at our next webinar thank you have a good rest of the
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