Last week Findacure hosted a webinar explaining the complex medical research field that introduced the different stages of pre-clinical and clinical research necessary to get a treatment available to patients.
The first talk focused on pre-clinical research and was presented by Oliver Timmis from the AKU Society, a charity that supports patients with the rare condition alkaptonuria.
Oliver explained that assessing a potential treatment of a condition by a drug starts with pre-clinical research. Pre-clinical research in drug development aims to show that a drug is safe and effective in a non-human model before human research is initiated. The drug development timeline is time consuming, taking 16 years on average from the discovery of a drug to having it as an available treatment for patients. The timeline starts with several years of pre-clinical testing and then clinical testing in different phases. Pre-clinical testing is quite variable, compounds are narrowed down at this phase with just a few going to clinical trials – this has very high costs (~$1 billion net cost invested over 15 years).
Pre-clinical development was defined as the testing of promising candidate compounds to ensure that they are:
- Likely to be effective
- Safe
- Sufficiently stable
- Excreted safely from the body
Around the world there are regulatory guidelines by agencies such as the FDA and the EMA that help in the development of effective pre-clinical and clinical research.
Animal studies are widely used in pre-clinical research, in fact, they are a legal requirement for any human drug developed in Europe. Animal studies are a standard procedure but controversial, therefore, ethical guidance for appropriate use is in place with systems such as the principles of the 3Rs.
Research can be divided into two categories – Basic and Applied/Clinical. Basic research aims to discover facts about how and why things occur without any relation to clinical outcome; applied research uses information generated by basic research to treat and prevent illness.
You can find BHD-specific basic and clinical research in the BHD Article Library.
Before pre-clinical research there is a period of “pre-pre-clinical research” to establish a target, to choose a molecule that is likely to work, act on symptoms/pathways most important to patients, and work out how to measure if this molecule is having the expected effect.
A classic type of pre-clinical studies is toxicology studies. These studies are usually performed in animals to support human studies. Important considerations are which species and how many animals to use. It has to be practical and the duration of studies should not be too long since the idea is to get to clinical studies quickly.
Toxicology studies are conducted to assess:
- Toxic effects following single and multiple dosing
- Effects on reproduction
- Potential for teratogenicity
- Peri/postnatal effects
- Potential to cause cancer and genetic abnormalities
- Effects in the immune system
- Potential to cause skin and eye problems
There are acute/short term toxicity studies which look for effects over short periods using the route of administration intended for humans. Usually, animals are observed for 30 days for eating/drinking habits, weight change, toxic effects and psychomotor changes. Subacute/subchronic studies, uses repeat dosing aligned to intended human usage. Testing over 90-180 days is required to support human administration for 1 week. For a chronic human illness testing over 1 year is required in animals
Definitive animal studies define the No Observable Adverse Effect Level (NOAEL) – the highest amount of drug used with lowest side effects. There is the need to use most sensitive species available and to consider the treatment regime.
An important tool used in medical research is the biomarker. Biomarkers are surrogates for problems in the human body, changes in biological systems that are related to exposure to a toxin. To be useful in pre-clinical studies biomarkers should be chemical specific, quantifiable at low levels, and the ability to be monitored in a non-invasive way is an advantage. Different types of biomarkers include biomarkers of exposure, of response effects and of susceptibility.
In summary, preclinical studies are undertaken to ensure that medicines are safe and effective. Success in preclinical studies means that a drug has been demonstrated to be probably effective, safe, sufficiently stable, and excreted safely from the body. Then agreement from the regulators is needed before moving on to clinical research (testing in humans).
Clinical research, the second part of this webinar will be discussed in a future blog.
You can watch the entire webinar here.