How a vaccine is made
A schematic approach to understanding Clinical Trials and Drug Development
With Covid-19 affecting each of our lives in some way or another, all of us are eagerly waiting for a vaccine. For many outsiders, the clinical research flow may seem a little too confusing. So let's take a bird’s eye view of how a drug gets to the market from being discovered as a potential candidate and how the people behind each of the stages are essential for ensuring the safety and efficacy of the drug.
The major organizations involved are:
- Sponsors: The pharma company or the university that discovered the potential candidate molecules for a vaccine. Industrial sponsors typically do not require third party funding, but academic sponsors like universities usually acquire funds from grants like the NIH. They prepare the Protocol that is to be followed by the Investigators and the CROs.
- Investigators: These are the clinics or sites that carry out the actual research. They are responsible for providing the right patients for each of the three phases of the clinical trials. They employ Principal Investigators (PIs), Clinical Research Coordinators (CRCs), and Clinical Research Assistants. Essentially, the CRCs are responsible for carrying out the bulk of the data collection with the help of the Assistants. They are the ones who get the patients’ vitals, administer the investigative product (the drug being studied), and monitor any changes to the patients’ health. PIs oversee patient safety and any other ethical concerns that may be a problem during this stage.
- Contract Research Organizations (CROs): CROs are the ones that manage the Investigators. Some sponsors may have in-house CROs but this has largely been outsourced since the 70s. They are responsible for recruiting the right Investigators, ensure that the right kinds of patients are used for the study, ensure that the data collected is robust and that the Protocol has been followed correctly by the Investigators.
- Food and Drug Administration (FDA): The FDA is the national organization to ensure that the drug is safe and effective. Before it can be released on the market, the Sponsors must be issued an NDA (New Drug Application) by the FDA. They are also consulted by the Sponsors before the Protocol is prepared. This would include the kind of evidence that they may deem necessary in order to evaluate the drug’s safety and efficacy.
- Institutional Review Board (IRB): This is an independent body that has the sole purpose of ensuring ethical guidelines are followed throughout the whole process. It has no interest in the success of the drug and is, therefore, a dedicated unbiased committee responsible for overseeing patient safety.
After a new drug has been discovered and tested in vitro and on model organisms like rats and primates, the Sponsors apply for the IND (Investigational New Drug Application). The Clinical Trials start when the FDA is satisfied with the lab results, develops the Protocol along with the Sponsors, and issues the IND. There are four phases that follow:
Phase 1: Usually, around twenty to a hundred participants are chosen. These participants must be healthy. For around two days up to typically a maximum of eight weeks, these participants are administered the new drug and monitored for any adverse side effects. The dosage is increased during every administration to determine the maximum tolerance limit, which is often the primary objective of this phase. Participants are highly likely to experience health issues during this phase and are thus required to be compensated financially.
Phase 2: This is the first time when the investigative drug is administered to a real patient, for whom the drug is targetted. Unlike the first phase, where the primary objective was to determine the range of dosage that can be safely used for a healthy body, the primary objective of this phase is to determine the efficacy of the drug on patients’ health. However, patient safety is still a closely monitored priority, in general, like the rest of the process.
Double-blinded studies using placebos are carried out on around a hundred to three hundred patients typically via ten to thirty Investigators. These last anywhere between two to six months, tentatively. Patients are monitored for any effects throughout this period and if the patients who were administered the drug show signs of improvement when compared to the placebo groups, we move on to the next phase.
Most candidate drug compounds fail in the first two phases of the trials. Each phase costs millions of dollars to the Sponsors and takes years to complete.
Phase 3: This is basically a larger scale of the phase 2 trials. Around two hundred to a few thousand patients are used, each being given either the placebo or the real drug while maintaining double-blinded status to minimize researcher biases. There may be another group that is administered the currently available drug from the market in order to compare how the new drug performs compared to the older one. From phase 1 and 2 trials, scientists have a better understanding of how the drug works and may now have a wider range of criteria for patient inclusion. This cohort is more representative of the target population of the drug.
This phase can last anywhere from six months up to five years, usually. After the first experiment, the placebo group may choose to actually be administered the real drug which would last another five years (if that was the initial time-frame). During this time, the first cohort is also monitored for any long term effects. If, after all these trials, the data suggest that this investigative drug is safe and effective, the FDA will issue the NDA, and the drug can be released on the market.
Phase 4: This is when the drug is being used by potentially thousands of voluntary customers. These customers are followed up by the Sponsors or CROs with surveys and questionnaires to better understand how the drug has affected them both in the short term and the long term. Any sort of positive changes are used by the Sponsors to better market the product, and if any negative side effects do arise, the FDA reserves the right to halt its circulation in the market and demand further investigations from the Sponsors.
So one may wonder if a typical drug development process takes ten to fifteen years, how biotech companies like Moderna or BioNTech or Pfizer are able to reach the third phase of the Covid-19 vaccine already.
The basic properties of the SARS-CoV-2 are very similar to other coronaviruses like MERS that have been studied for years. That’s why scientist were 10 steps ahead in the research phase of actually making the candidate vaccine molecules. The major bottleneck in the whole clinical process is the availability of the right patients. In the initial phases of the trials, because not much is known about the safety and efficacy of the drug, the criteria for recruiting a patient is very strict and narrow. But with Covid-19, as of this moment, a total of 63.6 million people have had it at some point, and about 1.5 million have died. So patient availability is definitely not an issue. The vaccine is probably one of the most well-funded drugs in history so the painstakingly long cycle of writing grants and getting them rejected and writing again was not the case this time. Some of the phases were also carried out at parallel to each other to save more time. Every step of each of the phases is being fast-tracked because this is a global emergency, which adds up and cuts the required time drastically.
When the vaccine does get released eventually, do not hesitate. Rest assured, that scientists will have done everything that they could to ensure its safety.
P.S. For more short and to the point articles on Data Science and how a biologist navigates his way through the Data revolution, consider following my blog.
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