Current Events: Questions and Answers Over Vaccines and Clinical Trials

[Secre]

I seem to spend a lot of time scouring Facebook and addressing concerns and fears over the latest coronavirus vaccines. So I thought I'd open a topic to see if there are any concerns here. Mods - I believe this would be permissible by forum rules, as we don't have the same strict 'no current events' rules that neopets have. If I have misinterpreted this, please feel free to remove. 

As some background, I have worked in clinical trials for a number of years (eight to my current reckoning, or at least there about) and know a reasonable amount about the background of trials. I do not directly work in coronavirus trials, although my unit has run three trials in the area within the last twelve months. I specialise in cancer trials and have worked on three large scale trials involving IMP's (investigational medications) across prostate cancer, small cell lung cancer and currently neuroblastoma in children. I did a brief stint in muscularskeletal trials where I largely supported non-IMP trials, which are trials that do not use any investigational medications and have also supported data collection in sample trials. 

The scientific rationale behind vaccines themselves is not my area of expertise, although I have a decent understanding. I do have contacts within the scientific community I can approach if anyone has any specific scientific queries I cannot answer. 

I'll start with some common concerns I have heard and can address from a trials perspective.

Has The Vaccine Been Made Too Quickly To Be Safe?

The short answer is no. The three drugs that are currently licensed as vaccines in the UK have all gone through Phase I, Phase II and Phase III trials, with robust and strict safety procedures. 

The long answer is still no, but comes with some more detailed information on how trials usually work. In the UK, we have to jump through a lot of hoops and a lot of red tape to even get a trial open for recruitment. The average time it takes for us to get a trial open to recruitment is between two and three years. This is because protocols and statistical analysis plans need to be drawn, we have to apply for and receive funding before we can even start looking for approvals, we need to apply for regulatory and ethical approvals, we need to canvas potential sites and get them interested before then setting them up, we need to set up contracts for each individual site and get data collection tools in place. This is an excellent guide to just how much goes on behind the scenes before we can get a trial recruiting: https://www.ct-toolkit.ac.uk/routemap/

In contrast, my unit has run three COVID-19 trials in the last twelve months - CATALYST, PACE and COVID19 BMT. Two of them were set up and recruiting in six weeks, one took slightly longer at seven weeks. This is unprecedented, but it is not unsafe. Why? Because the red tape was cut. COVID-19 has sparked such a wave of scientific, political and public interest that funding was being thrown around. approvals were being fast tracked and sites were clamouring to be included. Things that would normally involve months of waiting. took weeks or even days. Things moved quickly, but that doesn't mean the protocols or development plans were less robust; it means we cut out the waiting times.

Once we get a trial up and running, it can often take years to recruit enough patients to analyse the data. This is because we are often dealing with rare diseases or small sub-groups of patients. The BEACON trial is in relapsed/refractory neuroblastoma patients - neuroblastoma in children is rare to begin with, but the patients we are looking to recruit are advanced disease patients and that makes our sub-group even smaller and so it has taken us five years to reach 220 patients with over thirty sites involved. This is the same across many trials. We often have to recruit internationally to have a chance of hitting the recruitment targets.

In contrast. two of the studies I referenced have completed recruitment and are in analysis and the final one is nearing the end of recruitment. There are hundreds of thousands of potential patients as opposed to the handful we get in smaller trials. For the CATALYST trial there are only six sites involved and all are in the UK. There is no need to spend all the extra time opening international sites, because the target population is large enough to be done even with a small number of sites in the UK. Getting the patients more quickly means getting the data more quickly. It means follow up points can be hit in a fraction of the time as the patients are all in and receiving treatment.

So in essence. speed does not mean a lack of testing or a decrease in safety. If anything. the speed these trials have been opened and recruited is a testament to how smooth clinical research could be in the future.

How Can They Know What The Side Effects Are?

The short answer is that every trial involve a thorough Adverse Event Reporting Procedure to be in place before any drug is licensed. This is no different in COVID-19 vaccine trials. We are legally (and morally) required to collect data on potential side effects in any trial. The scienctific term for this is pharmacoviligence and it is taken exceptionally seriously within clinical trials.

The long answer once again comes with some more detailed information on how trials usually work. Every trial comes with an entire collection of Case Report Forms (CRF's) that are entered into large databases; these include:

- Pre-trial data such as pre-existing conditions and screening criteria. For cancer trials we also collect specific data such as tumour measurements and assessments to be assessed against later forms. 

- Trial data such as pre-treatment forms documenting the assessments done before each treatment, treatment forms documenting what trial drugs the patient was given, con-medication forms documenting what non-trial drugs the patient received at the same time and adverse event forms collecting every single sniffle, whiffy blood test and scrape and bruise. For cancer trials we also continue to collect tumour assessements for obvious reasons.

- Follow up data which are collected at set points defined by the trial protocol. We usually collect Adverse Events for 28 days following last treatment and then collect more basic data at set points. This may be every three months, six months etc depending on the protocol.

The Adverse Event Forms are the most crucial to this question though. Throughout any trial, we are legally mandated to collect data on every adverse event a patient may experience during the trial. This is not just side effects, this is every single event. So if a patient falls over and breaks their wrist, that has to be reported. If a patient gets a cold or a lung infection, that has to be reported. The full list of everything is here and it is pretty exhaustive even without the 'Other' category for anything that might fall through the cracks: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.

Throughout the course of a single trial, there will be hundreds if not thousands of AE's reported. Some of these will have no relevance to the trial; so if a kid falls over and breaks their wrist, that won't be flagged. But if ten kids fell and broke their wrists, this would be flagged for assessment as a potential concern for bone weakening with the drug. Some side effects are expected. others are not and it all comes down to what is shown by the analysis of the overall data. All of this data is analysed throughout and at the end of each trial. It is presented to a specific committee made up of consultants and experts in the field that looks at the unblinded data (so can see which side effects are only on trial IMP arms of the study) and makes a decision as to whether it is safe to continue.

In addition to this basic level of reporting, there is also a process called Serious Adverse Event/Reaction (SAE/R) reporting in trials. An SAE is any adverse event that causes hospitalisation, prolonged hospitalisation, is life-threatening, causes congenital/birth abnormalities or results in death. And these are taken incredibly seriously. Additionally, any SAE is also reported as a regular AE to ensure it is included in the main analysis data.

There are strict time frames associated with how quickly we have to report these more severe events to our reporting agency and all of these events are individually assessed by the site consultant and then by the lead investigating consultant on the trial. One of the assessments is whether the event is linked to the drug - if it's not, like that random kid who decided to fall out of a tree referenced earlier, then it is an SAE and we go about our business as normal. If it's could in any way be linked to the treatment, then it is escalated to an SAR (reaction rather than event) and then a second level of assessment is done. At this point it is determined if it is an expected side effect and this is where all hell can break loose. Because if we get an event that is not anticipated then this becomes a SUSAR - our acronyms become silly here and it stands for Suspected Unexpected Serious Adverse Reaction. The reporting time frames become even stricter and this is the kind of event that stops trials. If we don't have enough data, we have to assume the worst - which is why the Janssen and Oxford vaccine trials were both paused. Once more data comes in, the event can then be re-classified if it is not considered linked to the drug. 

What is important to note is that most trials do not collect adverse event data after a certain period - so in cancer trials this is typically 28 days. If there are any suspected SUSAR's however, these can be reported years after the trial has finished. What happens at this point is that the drug is (hopefully) licensed and the post-licensing period is known as the Phase IV trial. The drug is being prescribed and we rely on doctors to report any unexpected side effects via the Yellow Card scheme - https://yellowcard.mhra.gov.uk/the-yellow-card-scheme/. This is standard procedure for all new drugs.

it is important to note that actually the COVID-19 trials are more likely to have noticed any rare adverse events. This is down to the simple numbers game. Our Phase III trials recruit anywhere between 250 and 400 patients as standard; if there's a rare event that might be seen in 1 in 1000 patients, there is a high chance we will not find it. It will come out after the drug has been licensed, in the Phase IV stage. In contrast, the COVID-19 trials have recruited tens of thousands of patients. These are some of the largest and most comprehensive trials in the UK in modern history. The Phase III Oxford vaccine trial alone involved 11,636 volunteers, the Pfizer trial randomised 43,548 patients. They have enough patients to be pretty certain about the side effects.

The Success Rate of the Vaccine is lower than the Survival Rate of the Disease, Is It Worth It?

The short answer? Yes. If we can stop 90% of the population from even catching it, we will stop the spread of infection in its tracks. We will protect our families, who may be at higher risk than ourselves and we will protect ourselves from long term complications.

The long answer. Let's take this one in parts. First of all, the question doesn't really make sense. Even if the vaccine was only 50% effective, it would still be worthwhile. At 50% efficacy, that would half transmission rates and bring that dreaded R number all the way down. At the actual success rates which seem to be within 80-95% depending on the drug (the Pfizer drug trials show 95% efficacy, the Oxford drug trials show 70-90% efficacy depending on how the drug was administered), this would be a huge boon to decreasing infection rates in the population. That will in turn protect the highest risk members of the community; if there are less cases in the community, there is significantly less chance that grandma will catch it.

Secondly, whilst COVID-19 has an average survival rate of 98-99%, survival doesn't equate to complete recovery. Survival means exactly that, it means you didn't die. Death is not the only concern though, and there are significant long-term complications present even in patients who were in low risk groups. These include those left with long-term respiratory or cardiovascular damage, inflammatory disorders, and clotting disorders. We do not yet know how badly those effects will affect life expectancy and quality of life. Other long-term effects that may have a significant impact on health and well-being involve mental health, gastrointestinal effects and possibly neurological effects.

SARS is not the same disease, so any comparison has to be taken with a grain of salt, however there are many similarities and we know that there is a persistent and significant impairment of health status in survivors of SARS over 24 months -  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192220/ and that a significant percentage of survivors still had chronic fatigue symptoms 3.5 years after being diagnosed - https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/415378.

Essentially, it is important that you do not confuse ‘survival data’ with complete recovery. You have an excellent chance of surviving COVID-19 if you are not in an at-risk group, but the chances of also having long term medical implications after the fact are also high.

Will The Vaccine Change My DNA? Can I Catch COVID From The Vaccine?

Short answer; no and no. mRNA vaccines are new and hugely exciting as they are ground-breaking research, but do not change your DNA. None of the licensed vaccines include live viral particles, so you cannot catch COVID-19 from any of them.

The long answer is a little more out of my comfort zone in terms of the high science end, but can be explained fairly basically.

- The Oxford vaccine is a chimpanzee adenovirus vaccine vector which causes the common cold in chimpanzees. It does include a live virus, but it does not include live coronavirus. Essentially they modify the live adenovirus so it is unable to cause the disease in humans, then take the spike protein from the coronavirus and genetically sequence it into the vaccine vector. When this is injected, it primes the body's immune system to recognise and attack coronavirus if you are infected. 

- Both the Pfizer and the Moderna vaccines are mRNA vaccines, which have caused more of the concern on the DNA front. They contain material from the virus that causes COVID-19 that gives our cells instructions for how to make a harmless protein that is unique to the virus. After our cells make copies of the protein, they destroy the genetic material from the vaccine. This protein then primes the body's immune system to recognise and attack coronavirus if you are infected. So this vaccine does not alter your DNA or cause you to contract COVID-19.

It is also worth noting that whilst these RNA vaccines are the first to be approved for use in diseases, it is not new technology. Scientists and researchers have been RNA technology for a while and there are clinical trials using them in various cancer types.

 

Hopefully that has been of some use. I'm happy to answer questions where I can and to ask contacts for further information where my knowledge is lacking.

[oceanblue5333]

Wow, this is so informative and fascinating! Thank you for sharing this information, very helpful.  I'm up for the Pfizer vaccine next week as I am a healthcare worker and of course I have reservations.  But, knowing how vaccines work and also seeing the short term (and potentially long term) implications of Covid-19, I consider myself fortunate to have the opportunity to receive the vaccine.  I implore everyone to do their due diligence and research this to the fullest- then proceed with the best personal choice they come up with, hopefully one that will continue to protect themselves and those around them from this horrific illness.

[Secre]

2 hours ago, oceanblue5333 said:

Wow, this is so informative and fascinating! Thank you for sharing this information, very helpful.  I'm up for the Pfizer vaccine next week as I am a healthcare worker and of course I have reservations.  But, knowing how vaccines work and also seeing the short term (and potentially long term) implications of Covid-19, I consider myself fortunate to have the opportunity to receive the vaccine.  I implore everyone to do their due diligence and research this to the fullest- then proceed with the best personal choice they come up with, hopefully one that will continue to protect themselves and those around them from this horrific illness.

Thanks! It ended up being a little longer than I had planned, I must admit but I figured the extra information might be useful to someone at least.

I think if I had a choice, I would want the Pfizer or the Moderna vaccine as they have the best efficiency figures. I suspect we won't get a choice, it will just be whatever the local NHS Trusts have managed to get a supply of. The Oxford vaccine still have a good efficiency percentage though, just not quite as good as the other two.

I think part of the issue we're having with people refusing to contemplate having the vaccine is down to just how niche an understanding of how clinical research actually works is. If you don't work directly in the sector, it is expected that you will just trust the experts and in today's world, people don't trust the experts not to lie to them. I'm hoping that by explaining some of the nuances of the trial systems - not just here, but on a variety of public sources - I can improve understanding and hopefully reduce some of the fears people have about the vaccines. 

I live in hope!

[Angeló]

Im a doctor and a lot of people don't want to listen and understand these facts ... but thank you for putting it this way

 

[jellysundae]

Thank you for sharing so much info, Secre!

I see people are driving their surgeries nuts now by flooding the switchboards wanting to know when they're getting their vaccine. -___- Someone on the local news yesterday mentioned contacting my surgery and being told they haven't got any vaccines yet, so I won't be having to set foot outside any time soon! I shall sit quickly and wait to be contacted though.

 

 

[greenfrog]

WOW! This is an awesome gift of information!  I have gotten the first dose of Moderna and my sister got Pfizer. I agree with you. I hope as many people as possible get it. It's not just to keep us safe but to protect those at higher risk of death. Would you be ok with my sharing this on Facebook? Do you know if I can share this directly to facebook (vs copy and paste)?

Thanks again.

Becca

[Secre]

On 1/9/2021 at 11:32 PM, greenfrog said:

WOW! This is an awesome gift of information!  I have gotten the first dose of Moderna and my sister got Pfizer. I agree with you. I hope as many people as possible get it. It's not just to keep us safe but to protect those at higher risk of death. Would you be ok with my sharing this on Facebook? Do you know if I can share this directly to facebook (vs copy and paste)?

Thanks again.

Becca

I'm perfectly fine with you sharing to Facebook - there's a share button in the .... section at the top of the post I've just found!

I suspect I've got quite a wait before I'm notified it's my turn as I'm not in any of the high risk categories - my work in clinical research isn't patient facing, so I don't count as frontline staff.

On 1/8/2021 at 7:00 PM, Angeló said:

Im a doctor and a lot of people don't want to listen and understand these facts ... but thank you for putting it this way

 

Yep, I get a lot of people just refusing to listen. I've almost given up trying to persuade the real detractors, but hope that by putting key information alongside their theories, others might be able to get the facts rather than believing what they see on Facebook.

On 1/8/2021 at 9:01 PM, jellysundae said:

Thank you for sharing so much info, Secre!

I see people are driving their surgeries nuts now by flooding the switchboards wanting to know when they're getting their vaccine. -___- Someone on the local news yesterday mentioned contacting my surgery and being told they haven't got any vaccines yet, so I won't be having to set foot outside any time soon! I shall sit quickly and wait to be contacted though.

Well, that's better than the alternative of not taking it at all! Not good for the surgery mind you!!

I know several places got their vaccine doses last Friday, so hopefully things will get rolling. But as I mentioned above, I still don't think most of us will get them until March-April unless we're in the high risk groups!! My grandmother (in law) got her first doses already and she's in her 90's. My grandfather (in law) is waiting on further research data about contra-indications with warfarin I believe though!

[jellysundae]

6 hours ago, Secre said:

But as I mentioned above, I still don't think most of us will get them until March-April unless we're in the high risk groups

Because I have MS I imagine I'll be a little before others in my age group, but I'm still not expecting it too soon. During the flu jab shortage in the Autumn I got mine a couple of weeks after they limited it to the over-65s 'cause they were running out. So I guess that puts me just ahead of the "everyone else" category, lol.

I don't understand the detractors, and I'm truly grateful for that. It's like the deniers in America who are screaming that it's a hoax, as they are actually dying from it. That's terrifying.

[midnight_spell360]

On 1/11/2021 at 9:17 AM, jellysundae said:

I don't understand the detractors, and I'm truly grateful for that. It's like the deniers in America who are screaming that it's a hoax, as they are actually dying from it. That's terrifying.

You just described my mom's entire family, including an Aunt who is a nurse!  Especially now with the Delta variant-the ppl who are being hospitalized & dying in the US are the unvaccinated! My mom's family had a "reunion" that they expected her (and her children) to attend -a 30+ ppl event being held in a park but no one vaccinated & everyone refusing to wear masks! When my mom was first invited, she asked if any of her siblings who work in the hospital and schools were vaccinated and got blasted on their GroupMe chat like nobody's business. Then, she apologized for offending their rights to remain unvaccinated and asked if the CDC guidelines about wearing masks would be followed-especially for my Nana who is 79 yr.s old and not vaccinated (her other daughters told her that vaccines were bad) and poor mom got blasted again. So my mom gave up trying to get them to understand that this was an unsafe gathering and just deleted all the "conversation" and any "notifications" until my youngest Aunt called my mom to blast her one more time about how horrible a daughter she was for not coming to see Nana (her mom). Bc my mom was just listening to my Aunt screaming at her on the phone, (we could hear my Aunt's disgusting taunts & shaming), my older sister walked over to my mom, took it out of her hand, & told my aunt "You don't get to yell at my mother like this. I'm hanging up now and don't call back!" 

It is so crazy that they are this way and are so ready to fight us about the vaccine but won't even take simple precautions to keep my Nana from getting this disease. Why are they so toxic? *shrug* I guess I'll never understand it but it really does tear up a family.

[jellysundae]

@midnight_spell360 Your post is heartbreaking reading ;_; I just don't know what to say. I can only hope, for all your family, that they're building immunity without any tragedy occurring.