Dummy's guide to vaccine approval
Since centuries, 1796 to be precise, when the first vaccine was developed in this world, doctors used various methods to help people in suffering. None of them had any statutory organisation or established system to develop, test, approve the cures. Each of these pioneers took huge risks, even played around with lives, used animals and then humans before they created a solution. Today there are globally accepted regulations for any vaccine when being developed, which all countries including India need to follow to gain global acceptance.
The steps, broadly involved, are as follows.
1. Exploring, studying, collecting data on the issue
2. Initial clinical stage of tests, protocols that start
3. Clinical stage where actual tests start
4. Review by regulatory authorities
5. Review by peers, external agencies
6. Manufacturing including external contract manufacturing
7. Quality control
A formal official approval by any agency worldwide is always after ALL the 7 steps are completed, audited, and inspected. Some agencies like FDA are more stringent than others in this audit approval process.
The clinical stage is the most crucial. This often makes or breaks a development process. This is where a company with a big bang idea will either find a rainbow or stop further work. This stage is divided into different phases as below.
Pre-clinical (or laboratory) Studies:
The stage where a trial and error “mad scientist” game is played in labs, petri dishes, computer simulations etc. Where one asks – how would man live on Mars and start finding answers and test those answers. One decides things like – does one take the virus/ blood/ bacteria or whatever from a monkey or synthesise it artificially or take it from an infected human. Is it given as an injection, tablet, spray, ointment? The possibilities theoretically are endless but based on experience and knowledge these get decided quickly. But each decision must be validated for technical, commercial, and other feasibilities. This is where a lot of time and effort is spent.
As the FDA defines it - https://www.fda.gov/patients/drug-development-process/step-3-clinical-research
Phase 0
When one has created something that the team thinks is workable, doable, they still don’t know what it may or may not do. Remember Viagra? It was supposed to treat heart disorders and get people up and running. But it tended to get something else up and running.
In this stage fewer than 15 humans and tiny doses used to see what happens. Here time is lost because not all impact is seen immediately. Organisations must balance the time taken versus taking managerial decisions to progress to the next step. In normal circumstances longer time is taken, but with Covid-19 time was in short supply.
Phase 1
Here a handful, around 100 humans are tested and given different doses. Safety is unknown and participants are volunteers. Here a research team checks only for safety and not effectiveness. Impact at different doses, intervals, and many other variables that can have an impact on the safety of the patient. This again involves time but with COVID-19, that was short.
Phase 2
Here a few hundred humans are tested and the side effects, impact, other reactions are all noted and studied. Most importantly, every single stage, decision, action is documented. Historical data helps in fine tuning this stage, but this is where the real gold mine starts to get created. This is where the excitement begins for a research team to say Eureka.
Importantly if the statutorily approved gates are not passed at each stage, then further phases are not even taken up.
Phase 3
This is the most critical stage because the research team has firmed up on the dosage, combinations, treatment, as if the drug/ vaccine is being given to people for treatment. Here a few thousands of humans, even if limited are tested. At this stage a research team is fairly confident that the vaccine works but the question is – will everybody across society see the same benefit? How will it work on people with different racial characteristics, regions, lifestyles, health etc. Theoretically speaking the number of imponderables is many.
Think of it this way. A regional language movie has been a runaway hit. What if you remade the film in Hindi or English? – will the audience equally appreciate it or will it flop? While the comparison may seem odious, fact and logic are that when it comes to vaccines only a larger sample size helps a company decide on its efficacy.
This is where statistics also create issues. Every time a research team developing a vaccine has to go searching for volunteers, sign them up, maybe pay them, and they decide on a finite number. A team working in say Delhi may pick a X number of people living in Punjab/Haryana while a team in Bengaluru pick X number living in Karnataka/ Kerala. Technically and in practise Punjabi/ Haryana folks may show 80% results while the Kerala/ Karnataka folks may show 60% results. Who they picked also has an impact on the results! When anybody says 73%/ 85% efficacy they are NOT referring to the universal population, they are referring to their sample size selected. In the real world the vaccine that showed 60% results and deemed less effective may show 90% efficacy over a million users while the vaccine that claimed 80% may end up at 70%.
Think of it this way. The car you purchase is advertised as giving 25 kms/ ltr fuel efficiency but in real life you get just 18. That is because the car was tested under certain common conditions to create a benchmark. In real life traffic, load, driving style, road conditions all impact fuel efficiency.
Its only when there is mass usage that one gets to know the real results of any vaccine.
Phase 4
This is where the vaccine is sold commonly, marketed openly and companies have systems to keep a tab on the feedback. Long term impact maybe seen which may have never showed up in any of the stages.
Every country, every organisation must follow this process. There are no shortcuts except by executive order or technically called as Emergency Use Authorisation by a statutory body under a government or by expanding Phase 3 where an organisation is given access to a wider testing sample by following due processes. Every company gets its data vetted by independent experts during this process, but it is still confidential and not publicly released.
The crucial aspect to be noted is for any vaccine to get international acceptance by an organisation like World Health Organization (WHO) the manufacturer needs to follow the defined procedure at every stage and keep them informed. While manufacturers that seek international acceptance will follow this procedure, it is entirely possible that a manufacturer follows their local country norms before they decide to go global/ WHO. In normal situations almost all organisations will follow this procedure. The OVID-19 vaccines have seen exceptions to the rule for various reasons as it was declared as a global pandemic.
While the FDA of USA is considered the gold standard for systems followed in this industry globally, any manufacturer not seeking international acceptance from day one cannot be tarnished as a fly by night snake oil seller.
Since the COVID-19 virus and its vaccinations are still new, far more data would be needed before any vaccine made globally is formally approved. As of end 2020 even the global majors have NOT shared data publicly but have shared the results but have shared data with independent experts as part of the approval process and organisations like WHO. The demand and argument that the Indian vaccine has not shared data is fallacious because it is vetted by independent experts who contribute to its approval process as required in India. The public at large cannot stake a claim for the data and critics claim that data is not shared. The manufacturer decides when they will submit data and results to an international body like WHO and unless they can pass that gate, nobody globally will accept the vaccine however effective.
How does the approval process work and what is the impact?
The work done by any organisation, is always a closely guarded secret. The secret if known can cut in three ways.
1) It can be used against the organisation with negative reports, comments etc by vested interests
2) The information can be used by a competitor to solve their own problems, speed up their work
3) It can be used to delay their work so that a competitor can capture the market first.
While at every stage organisation go through local country internal processes, manufacturers who work globally with organisations like FDA, must get approvals in the interim for carrying out certain work. The organisation would need approvals for each stage. Their documentation and rigour of investigation is examined at every stage. Even then formal approvals are given only after the manufacturing facilities are also inspected, audited, and overall documentation/training is verified.
Often a vaccine developed by a particular organisation/ country may use an already globally/ FDA approved manufacturing facility in a different country as a contract manufacturer.
It is only when an organisation has jumped through all the stages, that they get formal approvals. It is only when an organisation is confident that they have TOTAL CONTROL over what they are doing, what they plan to achieve, that they will release data, information, documents, results to the wider public at large. Each organisation decides that for themselves. Their decision is driven by what they see, observe, happening around them. Not necessarily because they have something to hide.
Think of it this way. Viagra in 2019 alone generated over 500 Million dollars revenue. Now imagine if they had released data on their work PUBLICLY, BEFORE, they realised the significance of their “failure”. Every other company would be running laughing all the way to the bedroom so to speak.
The bottom line – Data is crucial. Data is the new oil. Facebook, Google, or Twitter monetise our data while we live in that illusory world thinking they are free. They have a 24x7 access to us without our clothes on, our opinions, tastes, plans, problems, desires - why would they charge us for that? Users should be charging them.
Never confuse DATA with Results. Results is the marks card after an exam. Data is the answer paper that shows where one was smart and where one was an idiot. Competitors want to know the latter, not the former.
In the case of the COVID-19 Vaccine every single company has created the vaccine in double quick time and world over none of them have obtained formal approvals. Different countries have followed different methods based on their situation – economically, logistically. While USA authorized the usage/ sale of Pfizer etc as an Emergency Use Authorization (EUA) by the FDA others allowed the wider usage of Phase 3 trials to help their countries. Even Pfizer got access to a larger sample during the Phase 3 trials, and nobody objected let alone term it an approval.
The USA post 9/11 brought in changes to the FDA systems and the phrase “Emergency Use Authorisation” was coined with specific guidelines. You can read more about this here Emergency Use Authorization | FDA . Other countries like India do not have such specific phrases which often leads to confusion.
USA has placed an order worth 2 billion $ for 100 million doses. Considering that a global population of 7 Billion needs to be vaccinated within a defined time the potential value of the vaccine business is 250 to 300 Billion dollars. Any large business opportunity, especially time defined will involve business lobbying, political interests, national interests, national security, bargaining strategies, and all of them even coming together as a perfect storm. Right now, a lot of decisions, the constant flip flop on advisories, which should be purely scientific have had an element of political/ national/ business strategy built in in every single country. That is reality. Read below linked news items, though one of them is a bit old.
The important thing is to not get confused by these noises and understand the subject from a scientific, systemic, and logical viewpoint but also see the deeper economic geo-political issues involved.
A lot of interesting reading is from the links below right from the global politics to business to comparison of procedures in different countries.
https://news.yahoo.com/covid19-vaccine-astrazeneca-pfizer-moderna-second-shot-naci-230829766.html
https://clinregs.niaid.nih.gov/country/india/united-states#_top
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