With lockdowns and death of social life, I have taken to Twitter to vent off my frustration with the way the British government has been handling the Covid-19 pandemic. But, as my screen time increased so did my frustration with the amount of misinformation that it out there on many scientific questions and one of these is how the drug development process works. So, I see it fitting to shed some light on how the sometimes very precious medicines make their way to you.
The drug development industry is one of the most if not the most regulated industry in the world, all aspects of drug development from the conception of the molecule in the laboratory to the day the last patient in any clinical trial has taken the medicine have to be documented, inspected, reviewed and contested before any medicine gets the green light to be marketed and then make its way to the patient. The reason this industry is heavily regulated is due to some disasters that happened in the past from the Nuremberg trials where Nazi doctors were conducting human experiments on concentration camp prisoners to the Thalidomide scandal to name just a few.
The first step in the development for novel therapeutic molecules is to make sure they show efficacy which is another way of saying that they have the potential to treat an ailment. This is usually done in vitro, if there is a glimpse of evidence that the molecule has a beneficial effect, animal studies can be the next step in the process. These studies will have to be conducted according to guidelines, and the safety of the product has to be assessed in these models. For some indications, there exist animals exhibiting symptoms of the studied condition but these are not available for all indications. Experimentation on animal models is conducted by utilizing multiple concentrations and multiple dosings of the product under investigation. If the animal data show that the product has the potential to be well-tolerated, then the move to clinical trials can be considered.
The move to the clinical phase of the development is when regulatory agencies such as the FDA which act as the police of the pharma industry start getting involved. For large companies with extensive development experience, the move can be smooth as they have an army of staff with all expertise required. For smaller companies, regulatory agencies tend to take them by the hand offering them incentives, reduced fees and scientific advice. The latter procedure is when the company has a set of questions on the drug development process that they would like to discuss and get validated and through this procedure they can tap into the expertise offered by regulatory agencies around the world. It is of note that most if not all sovereign countries around the world have regulatory agencies. The G7 countries have the largest and most experienced staff but countries rich and poor have committees in place to study and decide whether to approve procedures based on the evidence presented in documents submitted by pharma companies.
For any company to start a clinical trial, a dossier needs to be compiled this is called the clinical trial application. In this application the drug developer needs to have the protocol that is like a manual to be followed by investigators (clinicians) and staff at the sites where the clinical trial will be taking place in addition to other technical documents detailing the efficacy and quality and safety tests that have been conducted to show that the product is fairly safe to proceed to usage in humans.
Phase I trial is the first-in man, this is the riskiest of all phases for participants, and it usually is conducted on healthy volunteers unless it is unethical to do so (e.g. drugs known to have serious side effects that a healthy patient should not be exposed to). This phase usually focuses on showing safety and involves a small number of volunteers. The drug developer needs an approval from each nation where the trial takes place. This comes after studying the dossier submitted and getting an ethics committee involved to approve the trial. Ethics committees look at whether the way the study is designed ensures the safety and integrity of trial subjects. They have doctors, lawyers, as well as patients in these committees. Not many nations allow phase I trials to be conducted on their people but countries in the EU, as well as the US and Canada and South Korea do allow phase I trials because they can monitor patients in case of serious incidents following the administration of the drug.
If all goes well, then the drug developer can move to phase 2, which is a larger trial where both efficacy (proof of concept) and safety are assessed. Some phase 2 trials are used to identify the best dose (safest and most efficacious). These trials are usually multi-center conducted in several countries around the world. An approval needs to be received for this phase from each regulatory agency in each country where the trial is conducted.
If phase 2 trials show evidence that the drug under investigation has the potential to show some efficacy in a larger population then the move goes to phase 3. This phase is a decisive phase in dug development. A huge proportion of trials do not make it past phase 2, but once phase 3 starts, there is a lot at stakes. The trial in this phase are usually designed to show efficacy either in comparison to a placebo (rare these days) or another drug that is thought to be not do good and is already in use by doctors. Phase 3 trials can include even 40-50 countries, with multiple sites in each country. The same process of approval is needed as in phase I and 2, but at this stage, more animal and human data is available and drug developers are scrutinized more by the regulators. Approvals can take months to be handed to them by regulators.
In general, trials can take from 1 to 4 or 6 years, and the length varies depending on the indication to be treated, the prevalence of the disease and the speed of recruiting the patients. Rare diseases are very hard to recruit for and trials for these would only include 10-20 patients sometimes.
If all goes well, and it seldom does, the drug developer now has data from phase 3 trials to suggest that the drug is efficacious and superior to either placebo or standard of care. To show this the trial would have been designed to include enough patients (powered) to show that any difference between the treatment group and the placebo group could not be due to chance or in other words proving that the null hypothesis in wrong.
During the clinical trials, the drug developer would have started to has to prepare a marketing authorization application. In this application all the details of the development need to be documented. This is a colossal dossier especially if the drug is a novel molecule. The experts in the agency make sure that all the guidance laid out by the regulators (e.g. FDA and EMA) have been followed and that the quality of the product is ensured as well as safety and the claimed efficacy can be verified. Questions are asked by regulators at every step of the process, and every regulatory agency can have its own questions that need to be answered in a timely manner with very tight deadlines.
If the evidence to suggest that the drug under investigation has a favorable benefit/risk profile i.e. the benefits from taking the drug to treat an indication outweigh the potential risks associated with it, the drug receives a marketing authorization or a license and can be marketed. However, it does not all stop here, pricing and reimbursement have to then be negotiated with governments around the world before the product can be placed on the market.
The whole process takes years and years, but for serious diseases like cancer, the process can be sped up as there is a potential for accelerated reviews if drug has the potential to save lives as is the case with Covid-19.