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When risk meets your children




Should we vaccinate our children against COVID-19?

What's the difference between deciding for yourself, and deciding for your child, when it comes to medical interventions?

Why didn't anyone at parenting school tell us we will have to make such difficult decisions?


The disease you never heard of, and the disease you hear about all the time from the perspective of a father of three, and an insider to the pharmaceutical industry.

Epidermolysis Bullosa- the disease you never heard of

My daughter suffers from a devastating skin condition called Epidermolysis Bullosa. How devastating? Enough for the doctor at the ICU to tell us she will not survive the age of two. She was missing parts of her skin when she was born, and was soon diagnosed with this extremely rare condition. In this condition, the skin is very fragile, so it gets painfully bruised, from even the most minor friction. Luckily and thankfully enough, that doctor was wrong about us, and she is now 10 years old, dances Ballet and is wonderful overall. She has many difficulties due to her condition, and so do us, but she has what is considered a relatively mild case. I asked for her permission to post this, after our many discussions around the dinner table about development of new drugs and about medical risks, especially in the past two years, where the global pandemic has brought pharmaceutical development to the headlines.


To some extent, that doctor could have been right. The severely ill with this condition don’t survive the age of two, and others suffer a life full of enormous amounts of pain and suffering. When you face such atrocities, you come to realize how incredible our body is- built accurately to the level of one single amino acid. And when some genetic mistake happens in a letter, a person is condemned to live a life completely vulnerable to the physical world.


If you want to learn more of Epidermolysis Bullosa and help raise awareness, I invite you to:

  • Take a look at this infographic brochure

WHAT IS EB
.pdf
Download PDF • 3.75MB
  • Visit DEBRA, the main international organization that helps EB patients, their families and caregivers


 

Reflection box on the urge to share wisdom with others


The urging question which remained to me (as a parent mainly) is why did that doctor decide to share with me his prophecy on her life expectancy. Be it true or false, why at that specific moment? Or at all?


There is a beautiful verse, based on the Buddha’s teachings*:

If it is not true, and not helpful- don’t say it.

If it is true, but unhelpful- don’t say it.

If it is not true, but helpful- don’t say it.

If it is true and helpful- wait for the right time.

The doctor’s remark, in my view, was both not true and not helpful, and certainly came at the worst conceivable time.


It is not true, because he had no grounds to determine the severity of her illness so quickly, when she was just born. I don’t need to elaborate why it was also not helpful, but I can only say that regardless of the "life expectancy", our daughter(s) taught us the value of appreciating the present moment as it is. We still joke about going to the hospital and “show him” he was wrong, but with this smile, comes a lot of salt from unnecessary painful memories.


A geneticist once told me that what we have is extremely rare, but at the same time, it is quite common for people to have something rare. The mere fact we are here, is already one hell of a statistical fluke, lets stop for a second and appreciate it, and not run around telling other people what we think will happen to them in two years!


* Buddha said it first, but I heard it from Steven Folder, in his wonderful (Hebrew) book, “Erut”. Highly recommended.

 


Ever heard of COVID-19 ?


Jumping the other extreme, COVID-19- most likely the largest pandemic in human history. Never before, did everyone get so excited talking about emergency use regulatory pathways and cold supply chain logistics . I found those topics exciting much before the pandemic, but none of my friends would listen!


So lets have a look at a common decision facing many parents: to vaccinate or not. What did we eventually decide for our daughters, in the context of risk and parenthood? Roll your sleeves please, its work time.


In the early days of the vaccination campaigns, my parents were the first to be eligible for a vaccine. When deciding if to take it, they faced a different risk profile than today: there was very little known safety data (aside from passing Phase 3 clinical trials, it was still very new, and the rare side effects were not yet known). On the other hand, it was already well known that they faced a significant risk of catching COVID and experiencing life-threatening complications. So the risk balance shifted heavily towards taking the vaccine, and so they did.


To vaccinate myself, the decision was relatively easy. At the time, the vaaccine already seemed very safe while the pandemic was still at its peak. The vaccine was still approved as an emergency use, but COVID turned out to be quite nasty- although much less dangerous than for the elderly- the long-term effects and unknows are worrying, So, in this case, the risks were reduced on both sides, and still, the balance was clearly to the vaccine side, so getting vaccinated released me (at least in part) from the fear of catching COVID or passing it on to others.


Since then, we had plenty of time to think about the day children will be eligible for the vaccine, here is a summary of our own family risk assessment:


The available data said it loud and clear: the vaccines are very safe, and side-effects were similar to other vaccines. In general, vaccines (today) are one of the safest medical interventions we've developed, and COVID, as it turns, is not so “safe” for children as it was originally thought. Its true that mortality rate of children is zero, but we hear more and more of the potential long lasting effects and the neurological involvement which is yet to be fully understood. To me, as a parent, this sounds scary enough, and is plausible given the violent nature of this virus. So, with a unanimous international regulatory approval at hand, based on the safety data from hundreds of millions of people worldwide who already got vaccinated, and the unknown effects of children catching COVID- we decided once again, that the balance shifts towards the vaccine, and we vaccinated our daughters.


We must appreciate that this is not an obvious or automatic decision, and I understand the fear people have to jump into this wagon, especially when they are not in the details, and even more so with their children. A solid risk-assessment is based on solid knowledge and information, and in today's world, we have an extreme contamination of the information we all receive. It is much like the microplastic we surrounded ourselves with. With regards to rare-risks we have not yet realized, we will all be smarter in a few years, when more data is available, but this will always be true for every decision in life- we can only work with what we know in the present moment.


The larger picture, of course, is public health and protecting the unvaccinated. In most cases, the self and the collective health measures, align well, especially with vaccines and the currently regulatory framework and ethics. Nevertheless, a personal risk-assessment is always done (even if unconsciously), and it is crucial to select our information sources very carefully. As we all know it is complex and creates a lot of misunderstanding, misinformation and fear.


Still, we must face that there is no such thing as a zero risk medical intervention. Just like there is no other action in life which is zero-risk. In this sense- choosing inaction (no vaccine), is similar to action, as far as risk assessment is concerned (i.e., there are risks associated with both pathways).


Risks are intangible and many times unpredictable. We are humans, and our decisions are inaccurate to say the least, but this is a feature, not a bug, as reality is continuously changing. The COVID reality is that the vaccines are very safe, they protect us to some extent, and to some extent they do not (especially with the new variants- the effect is very hard to pinpoint). We see that the immunity fades overtime and boosters are needed (even though we hoped we wouldn't!), and the situation evolves all the time. So whatever it is we decided today, by definition, will be inaccurate tomorrow. As parents, as humans, we must make inaccurate decisions on a daily basis, because risks are unavoidable, and reality is unpredictable- c’est la vie!


 

Reflection box on Parvo and other “common viruses” and risks


My middle daughter was offended by her absence from the post (the youngest doesn’t care yet 😊), so I decided to add another reflection box on Parvo virus. Parvo is a virus known to be dangerous for dogs (so they get vaccinated for it). It has a much milder Human version, Parvo B19. It causes a typical viral illness (fever, fatigue), and also follows with a typical rash. It is very common and generally not dangerous.


My daughter was ill with a general “virus” diagnosis, and passed it to me as well. We both spent a few days crushed on the sofa with fever and fatigue. The doctor told us there is not much to do, “it’s a virus” (which is the most dreaded diagnosis every parent knows very well). He did instruct us to get a bloodwork in case symptoms don’t go away in a few days. After three days, it seemed to not be going away, and it was almost the weekend, so I dragged myself and her to the clinic to get us both a bloodwork. Two hours later, they call us to urgently go to the hospital- her Hemoglobin was around 3, which I then learned is just about the level that a person may not survive to tell. 30 minutes later, the girl is half faded away, in the ICU, where they give her an emergency transfusion which saved her life. As the sigh of relieve arrived a couple of days later, and she was no longer in danger, I developed a full body rash, classical of the Parvo disease. This has helped the doctors discover that she has a rare blood condition in which the blood cells are not well formed, so her body destroys them and makes new all the time because it thinks they are faulty. It just so happens that Parvo infection causes a significant slow down in the production of new blood cells- this plus that, and you have an infant losing red-blood cells in an extreme pace without you knowing it.


Had they offered me a vaccine for Human Parvo beforehand, would I say yes? I don’t know, but they haven’t offered me this because simply there isn’t one. Parvo is not dangerous to the majority of people, and it doesn’t make sense to develop a vaccine just for the rare cases that would complicate. Still, as with any risk, you never know which side of the coin you will get, even if it is a 1 in a million chance. Ever heard of Epidermolysis Bullosa?

 

The regulatory perspective


The decision to vaccinate (and to any medical intervention) is a classic risk-based decision: There are risks all around us- the disease itself- the risk of getting complications (which is age-dependent), the impact of isolations on our lives and of course- the potential side effects of the vaccine, common and rare.


This is the framework in which the regulatory authorities think about approving any drugs. What is the disease at hand? How many are suffering? What is the proposed drug (Safety and efficacy)? What are the alternatives? All these are very complex to answer, and in order to do this as accurately as possible when people's lives are at stake, the authorities must follow a formal risk-based and science based approach in deciding.


In order to do that, the regulatory authorities employ thousands of professionals, who’s jobs are to go over all the different details of the vaccine (and any drug): What is its safety profile- side effects, common, uncommon, how effective is it? Is it worth the risk? how is it manufactured? Can it be supplied safely worldwide? Interpreting this data in today’s world of advanced technologies is a positive feedback loop between the industry and the regulatory authorities.


So they examine the situation at hand and perform a science-based risk assessment. The outcome is always acknowledging the level of residual risk which is entangled in the decision. So in translation: the authorities- by authorizing a drug- tell us we can take it, they assessed that it is good enough given the alternatives, and the risks are worth it.


The miracle cream and mRNA vaccines


How is it all related to Epidermolysis Bulllosa, you might ask?


Well, think of the anticipation and hope I have as a father, as a family, that one day they will find a cure for my daughter’s disease? Imagine she will have a cream to put on her skin, which would make it strong again. Would you not consider this a miracle cream?


We’ve been watching the different Biotechs developing drugs for Epidermolysis Bullosa over the years. Some rose and fell, some followed through with treatments that ameliorate the condition but do not solve it, and others are pursuing the treatments that would cure the actual disease by means of genetic correction.


One notable example is Krystal Biotech, who rose like a meteor just seven years ago, and made it in remarkable time to where they are now (topline Phase 3 results). They are the ones developing the Miracle Cream described above. It is based on genetically modified Herpes virus that carries the correct copy of the damaged gene. By infecting the patient’s cells, the virus delivers a healthy gene into the cells, and they start making the protein correctly (because now, they have the right instructions). See infographic about their platform here.


In some sense, this is similar to the mRNA vaccines, in which we utilize the cellular machinery to make a foreign protein (this time: the Spike protein). The cells create a very accurate spike protein- just like the real COVID would, had it infected that person (same instructions, different carrier). So the immune system gets the best antigen to learn from and build the immune response in advance. It is also “weird” enough to evoke an immune response. Classic vaccines, in which the foreign proteins are manufactured in a bio/pharmaceutical process, try to make the proteins as closely resembling the “real thing” as possible, but they don’t always get it 100% right and the immune response is sometimes insufficient (the system doesn’t get overly excited about this foreign material and/or creates a response which is inefficient against the real thing). Moreover, making these products in pharmaceutical grade and fast is more complex, especially in the X Billions scale the current vaccines are required.


Taking risks


So both products- the mRNA vaccines and the Miracle Cream, are new products. The COVID vaccines were an easy shot considering the overall situation. But what do we do with the Miracle Cream? Do we give it to her as soon as it is approved? Or do we wait a while longer and see the reports on side-effects in real-life population? Remember she is a mild case. Are we willing to risk it? What if it gives her a rash? What if something rare happens? Will we know?


The phase 3 clinical trials of a drug like this are usually much smaller than for vaccines. The approval barrier is also much lower, due to the severe cases who are desperately waiting for this drug. The risks of living another day with severe EB outweigh the risks of a new drug most likely. But how do we balance the risks of living with a moderate case of EB?


Sometimes, a drug is approved only to severe cases first, so it could well be the situation here, but I really don’t know. Regardless, there will be a point in which we will have to make our own decision. Even though I am an expert in Biologicals CMC, and can read all the publicly available data the company publishes I will not be able to make "my own research" in full, and will have to trust the system to direct me to a right decision. The pharmaceutical company, the regulatory authorities and the doctors are all in charge of analyzing the data to the best extent possible and making a comprehensive risk assessment. We, the patients, will have to take a leap of faith when selecting to take these medicines, in hopes of a better future.


To summarize, risk is commensurate to benefit.


No matter if you are suffering great misery with a rare skin condition, and this new drug could be your ticket out or confronting a once-in-a-lifetime pandemic, and want to protect yourself and your loved ones with a new vaccine, you must make a risk-based decision and informing yourself is the basis..


The higher the stakes, the more risk we are willing to take, and the regulatory paradigm is more or less aligned with this concept. This eventually ties to the basic ethical principles in medicine:



Do no harm, help the suffering.




 

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