Published on November 2nd, 2020, by Labtoo's team
The life cycle of a medicine is extremely long and tedious: it has to undergo many regulated phases in order to ensure its safety, efficacy and quality for the patients. Here is what you need to know about the different phases of the drug development.
On 10.000 screened molecules during the exploratory research phase, only 10 drug candidates will be patented and 1 will manage to pass all the necessary steps to become a marketed drug: the road to innovation is long, complex and expensive. Each drug development follows a unique process in terms of drug identification, validation and optimization, preclinical and clinical studies and marketing.
The drug development process generally lasts for twelve years, with an average 10 years of R&D coupled with 2 years of regulatory procedures. It is also an expensive process: in 2012, a study estimated that designing a molecule would cost 900 million dollars, and 1.5 billion if considering the cost of capital.
This is the phase where scientists identify and isolate molecules that can be potential drug candidates: it generally lasts from 2 to 5 years. But how are these relevant molecules discovered?
Scientists have historically discovered new drugs by copying or being inspired by nature (that is the case, for example, of quinine or salicylates) or by serendipity (the most popular examples are penicillin or sildenafil). Empirical pharmacology then occupied a prominent place in drug discovery: one of the most used methods to discover drugs was to put substances from chemo-libraries in contact with cells or organisms to observe a therapeutic effect on them.
More recently, the notion of the biological target has marked a significant change in pharmacology0 in drug discovery. This relevant target (which can be a signaling pathway) can be found in the physiopathology of an organ or a disease mechanism, or functional genomic, by a bioinformatic analysis of healthy tissue VS diseased tissue genetic activity. The identified target can then be validated (or not) by a relevant molecule able to bind with the target and produce a physiological response.
These relevant molecules (also called hits) are isolated from high throughput screenings of chemo-libraries and other in silico modeling strategies. The next necessary step is then to identify a binding site and a pharmacophore by using NMR, crystallography, or chromatography techniques.
It is also during the drug discovery phase that begins the galeni development, thus defining choices in the drug formulation, production, and tests. Optimizing hits to ensure their efficacy, metabolic stability and bioavailability depend on the employed galenic form. This structural optimization and molecule synthesis can be done chemically or by bioproduction.
This first step in the drug development process is very expensive, with an extremely low success rate: almost 98% of drugs going through the development process do not make it to the marketing phase. Mainly financed by the pharmaceutical industry and governments, drug discovery also involves numerous interactions between academic researchers, manufacturers, investors, regulatory agencies, and patent authorities.
Preclinical research combines pharmacodynamics and pharmacokinetics studies realized on lead molecules obtained from the previously screened hits. This step allows researchers to select a limited number of drug candidates that can access clinical studies. The goal is to test patented leads on cell cultures ( in vitro models ) or on animals ( in vivo models ) in order to identify their efficacy, safety, toxicity, and pharmacokinetics characteristics – to validate the proof of concept of the drug candidates.
Tests have to be used according to the Good Laboratory Practice (GLP): these regulations specify which studies have to be realized and which animals have to be used during preclinical research to retrieve good data.
The safety profile of the drug candidate is established based on systemic and local toxicology, genotoxicity, carcinogenicity, and teratogenicity studies in animals. ADME (Absorption, Distribution, Metabolism, Elimination) characteristics of leads are also drawn up in order to determine the dosage range for humans during clinical studies.
Pharmacodynamics studies combine ligand binding screenings, dose-effect and time-effect studies, and therapeutic/toxic thresholds establishment in order to quantify the therapeutic effects of the drug.
On a hundred of tested molecules, only a dozen will enter clinical studies as drug candidates.
Additionally, a necessary step in the drug development process before it enters the clinical trials is to product it according to the Good Manufacturing Process (GMP). GMP ensures that the quality and nature of the tested product are known, in order to avoid any production changes that could trigger negative side effects on humans during the trials.
Clinical trials imperatively require prior permission to be conducted on voluntary human persons by the ANSM (French National Drugs Agency) and an Ethical Research Committee. Two elements are particularly important: the free and informed consent of trial participants and the authorization from the Ethical Committee.
Clinical trials are divided into three categories.
Phase I clinical trials are realized on a small number of healthy volunteers and allow scientists to approve the drug’s safety for human use. They consist in proof of concept studies. Pharmacological effects (dose ranges, maximum tolerated dose) are studied during this phase, as well as pharmacokinetics characteristics in the human body. They can last from a few weeks to several months.
Phase II clinical trials happen if results from phase I are positive and without danger to humans. They consist in testing the efficacy of the drug and its optimal dosage. They are conducted on several hundred patients, divided into two groups: the first is administered the active substance, and the second one receives a placebo. These studies can last from months to several years. On ten patented molecules tested in phase I and II, only two will be able to reach phase III. At the end of phase II, the R&D program will have lasted for about 8,5 years and cost around 1 billion euros.
Finally, phase III clinical trials aim to confirm the efficacy and the safety margin of medicine on an extended section of the population by including thousands of patients countrywide. The goal here is to study the drug’s risk-benefit balance and its precautions by assessing its side effects on a whole population. This is the longest and most expensive phase and more than 50% of medicines that reach this phase end up failing. If the trials’ results show a reasonable risk-benefit balance, a marketing authorization can be addressed by the pharmaceutical company.
The marketing authorization (AMM) allows the company to launch its newly produced medicine on the market, based on its demonstrated efficacy, quality and safety towards patients. Evidence of these criteria has to be compiled in a regulatory file called the Common Technical Document (CTD). The examination process by regulatory authorities generally lasts from 12 to 18 months. The medicine cannot be sold until authorities have not delivered the marketing authorization.
Numerous countries also demand cost-efficacy studies in the CTD in order to help governments and insurance companies to make up their mind on whether the medicine has to be on a prescription to be delivered and if it should be reimbursed or not.
The marketing process requires to communicate the collected information on the new medicine to physicians and other healthcare professionals, in order to inform them about the drug’s effects and how to correctly prescribe it.
However, the pharmaceutical company needs to collect and analyze data on the drug’s safety after its commercialization: this is the pharmacovigilance phase. This postmarketing surveillance includes phase IV clinical trials (conducted on the whole population) in order to detect and assess the drug’s serious adverse effects and understand its “real” risk-benefit balance.