Safe and effective

In the development of novel therapeutics, few words have received more attention than safe and effective, which received most attention in light of the Covid vaccines. Whilst under normal use these words are understood, in the context of therapeutics their meaning is less straightforward. Whilst the context of the Covid-19 vaccines will likely be a major focus for the readers of this article, I want to keep this as informative as possible for all medications - the truths about the various Covid vaccines will emerge in their own good time as they have for every drug.

Let us start with the first word, safe, in the context of therapeutics. Generically speaking, most of us understand that if something is safe then no harm should come from it under normal circumstances. There are numerous activities that are considered safe and yet accidents whilst doing them can result in harm, running and swimming are two good examples of this - on the whole they are considered safe and the benefits outweigh the risks under normal circumstances and with a small amount of common sense being applied. Safe under the medical context is not as clear cut and comes with the knowledge that all medicines carry risk that should be understood before you take them, that is why any medicine you purchase has a small leaflet inside that details this. This patient information leaflet must indicate the administration, dose, precautions and potential side effects of the medication.

Why do drug manufacturers have to do this? In short, because the law requires it. Any therapeutic must be understood in these terms and been shown to offer a benefit that outweighs the risk of its use - the aim is to relieve symptoms without incurring additional ones if possible. You may have heard the expression “all medicines carry risk”, whilst this is true, the timelines and extent of the risk varies by patient and by therapeutic. Anyone who tells you that their new medication carries no risk is simply not being honest. A more accurate statement would be that it carries no risk that they are aware of at this time.

So how do we define “safe”? In the first instance, you need to understand who your patient population is that will receive this medicine, for example, if your treatment is for Parkinson’s disease, then you know in general that your patient population will be elderly in nature although there may be exceptions for this disease (as with every disease). Under such circumstances, there will be acceptible risks for an ageing patient community that can be detailed in the patient information leaflet, examples might include loss of fertility which will have less of an impact on an ageing patient than a younger one. Targeting an ageing population for your treatment means that testing this drug on young and healthy peope will give a misleading understanding of its actual safety in the target population. So defining the target patient population significantly impacts how you test for safety and the criteria of acceptable side effects which patients must be be clearly informed of.

In the second instance, we need to be aware of the time window any side effects could manifest in, especially if we are aiming to treat younger patients. In the above example, medicines that affect child bearing capabilities in the elderly are acceptable however this same side effect would be unacceptable in the young except under significant risk to life where the benefit outweighs the side effect. Medicines that target younger patient groups must be shown to be safe regarding their impact on the mental and physical development of the children they are being prescribed to, this is a particularly tricky area and one that many companies choose to avoid as the impact of such medications may not be seen for decades and represents a grey area for predictive safety. Whilst for many of these examples, the risk can be identified early on, as our safety trials are setup to identify such side effects, the time window when they become evident presents a major challenge to clinical safety trials.

What if your side effect takes 20 years to develop? No drug on the market has undergone a 20 year clinical trial, western approaches simply could not tolerate such delays for potential therapies. This is what underlies many of the court cases we hear about against pharmaceutical companies - the single biggest factor is usually “did the safety data indicate that this was a risk” and if so was this made known? In some instances this was known or becomes evident later and if these data are ignored it usually results in large fines and payouts to the impacted patient groups. In other instances this only becomes known through post approval safety monitoring and will result in unforeseen side effects that are not detected in the safety process and do not represent any wrongdoing by the parties involved.

Lastly and most concerning, is understanding the impact a new drug has on any other drugs the patient group are taking. This is particularly problematic in elderly or compromised patient groups who may already be taking several other drugs, how does the new drug interact with the ones you are already taking? Is the safety risk of taking the mixture of drugs already known or tested? This can get very complicated and adds a lot of time and expense to any new drug safety testing if the target patient population are already medicated.

This is why safety is so hard to define: who is this medicine safe for? Have you tested it in these age groups, communities and patient groups? What drugs or treatments are safe to use alongside the current treatment and which are not?

The most difficult thing to define in safety terms are when your patient population is anyone and everyone, for the reasons detailed above, defining safety for everyone presents tremendous challenges.

Thankfully, “effective” is far simpler to define in the context of medical treatments - what should this drug do and has it been shown to do this? Clinical trials have been the last bastion of determining whether a drug actually works or not in patient populations. In early trials, phases 0-1, the new drug is tested for the first time in humans, to determine tolerated dose and assess any risks. Due to the investigational purpose of early clinical trials, they are tested on small groups of healthy volunteers and the groups are not randomized. Phase 2 clinical trials test the new drug on large groups of ill patients, to determine the short term effects and these trials are usually not randomized. Phase 3 clinical trials test the new drug on large groups of patients who are ill and its effects are compared to existing treatments or placebo and are randomized to ensure the results are not influenced by the trial teams. These trials involve thousands of people and usually last more than a year (for the reasons detailed above!). Phase 3 clinical trials determine whether a treatment actually works in patient populations as compared with standard treatments and placebo treated groups - what constitues actually working or not is defined ahead of the trial and cannot be changed once the trial has started. These rules are often bent by organisations who have failed to meet their clinical end points but do feel some good has come from the drug in the patient groups. The reality is that if a drug has failed its clinical endpoints a new trial will be required to demonstrate that it is effective, at great cost and following intensive patient recruitment for the next trial.

In some cases, clinical trials end early because the end points have been achieved ahead of schedule and with patients best interests at heart, the drug is moved to approval faster than planned - such changes to the process are reserved for serious and life threatening diseases where ethically patients should receive the best standards of care as soon as they are known and available.

If you are going to be prescribed any new medication, I would always advise reading the literature around it which will be in the public domain. You need to understand who the target patient population are, what are the known side effects and what its been demonstrated to do in a clinical trial setting. After that, as with so many things in life, the choice is yours to determine whether it could be right for you or not.