Question: My question for yourself is How do the multi-phase processes of drug development, including preclinical testing, clinical trials, and post-market surveillance, ensure the safety and efficacy of pharmaceutical products, and what are the ethical and scientific challenges that arise during these stages?

Kathryn Howells answered on 2 Apr 2025:

Wow that’s a good and tough question and sounds like you already know a lot about Clinical trials and the different phases involved. As you have already mentioned a new drug will be tested in a number of pre clinical trails before it is given to a human. As much as possible the testing will be done “in-vitro” so in a test tube as well as animals but this is limited as much as possible. I haven’t worked in pre clinical but my understanding is that these are small trials in labs, checking for signs that the drug is active and also for any toxicities. I’m a mathematician as opposed to a chemist or clinician so don’t understand how this is done during pre-clinical trials sorry.

If the drug passes the pre-clinical tests then the drug will pass onto clinical trials, initially Phase 1, where the drug is tested in healthy human volunteers or if this is not ethically possible due to accepted toxicities then it will be tested in patients. For example many cancer treatment are known to have side effects eg chemotherapy and so it wouldn’t be ethical to give it to healthy patients. However cancer patients accept the risk of the drug for the potential benefit it will provide.

The 1st trial (from my knowledge of working on phase 1 many moons ago) is called “First Time In Man”, which are very small, possibly 20 volunteers which will be assigned either the new drug or a comparator (could be placebo or the standard of care if placebo is unethical due to it being patients where there is a drug available for the illness). Extremely low doses of the drug will be given to check for any adverse reaction eg possibly a headache or sickness. If there are no adverse reactions across the patients then the dose will be increased slightly to again check for a reaction. The dose will continue to be increased until there is a cut off number with a reaction – say 5 out of 20 and is compared to the comparator drug to check for more reactions. This study provides information on the maximum dose that can be tolerated. Usually the higher the dose the bigger the effect but also the more likely for side effects or toxic results and so its a balance. The dose will then be tested in a number of different studies – eg repeat dose to check what the drug does to the body and also what the body does to the drug (known as Pharmacokinetics (PK) and Pharmacodynamics (PD)), this helps define things like how often you need to take a drug to still receive a benefit but without there being a build up of drug in your body that could potentially cause harm. There’s also drug interaction and food interaction trials to test if taking the drug is impacted by the presence of food or other commonly used drugs and inform whether the drug needs to be taken with or without food etc.

If the drug passes all the phase 1 trials in terms of it appearing to be safe and the PK and PD shows no concerns and stable results then drug moves onto phase 2 where the drugs are in slightly larger studies (eg 100+ patients) to test in patients that the drug is safe to use and provide an indication that it works. I’ve not worked on phase 2 studies to be able to provide as much information but the studies will be looking to confirm the PK and PD data seen in Phase 1 trials and also checking for adverse events and laboratory findings in patients on the treatment compared to a comparator. The studies will also be used to confirm the dose selected from the phase 1 study and to potentially test a slight lower dose before deciding on the dose to be tested in the next phase.

If there are no safety concerns the drug is tested in a large Phase 3 trial, these often include patients worldwide and often 1000+ patients and can last for many years. I wok on a drug for Cancer and so the phase 3 trials can be for over 10 years and are extremely expensive to run. Hence drugs are only tested in these trials if they have passed all the pre-clinical and phase 1 and 2 clinical trials. Again patients are randomised to the new dug and a comparator, usually the standard of care (if one exists) and for a very specific therapy eg non small cell lung cancer. These trials again check for safety through adverse events, vital signs and laboratory data collected during the study and also for efficacy, to test the the new drug improves the patients illness by an amount that is clinically meaningful. This is where statistics comes in, we measure the difference between the treatment group and the comparator group in a measure relevant to the illness (eg reduction in size of a cancerous tumour) and test the probability of observing the difference if the treatments had the same benefit, if the probability is small then we can claim that the new treatment does make a difference.

From an ethical point of view, during a long phase 3 trial there may be “interim” analyses set up that allows us to check the results early and stop the trial if the drug doesn’t seem to be working or even if drug is working better than expected so that we can get the drug approved early and available for patients to take. In this situation we still need to continue the study to check for a longer period that the drug is safe and is consistent with the early results. Also during the course of the study there will be an independent team of doctors that review the safety data to ensure patients receiving the new drug are safe. We can’t do that within my company as we don’t know what drug the patients are taking until the end of the trial to ensure the results are not biased.

The phase 3 trial, along with the results of the phase 1, 2 and preclinical studies are used to apply for a drug license to make it available for patients to use. If the drug is approved, there are usually extra trials (phase 4) to test the drug in certain smaller populations/countries or in Children etc. Plus the safety of the drug is monitored through standard use of the drug (ie in hospitals or prescribed by doctors) to ensure there are no new side affects or rare events that weren’t observed during the studies. If there are then these are added to the drug label or leaflet found in the medication box.

I hope that helps answer your question.