in drug research and development the patient is the main focus the mission for novartis is to help the patient overcome a disease and improve their quality of life the drug development process is designed to ensure that innovative new medicines are effective safe and available for patients in the shortest possible time the first step in drug development is to discover the best targets for treating or preventing a disease targets are usually proteins in the patient's body which are associated with a disease or proteins in microorganisms causing a disease the challenge is to identify which proteins are relevant and more importantly confirm their role in a disease increasingly novartis focuses on understanding cellular networks of proteins or pathways a single protein may transmit messages to several other proteins sometimes in multiple pathways affecting their function knowing how these pathways work and interact helps to identify the most appropriate target for a drug [Music] the pathway approach allows novartis to better understand the mechanisms of a disease this knowledge together with the desire to address unmet medical needs determines the priorities in target discovery in drug discovery several methods like high throughput screening and computer based design are used to find chemical compounds or biologics that bind to the identified target if a compound modulates the target in a way that is expected to alter the disease this so-called hit will be refined to improve its safety and effectiveness eventually becoming a drug candidate discovering and bringing one new drug to the market typically takes an average of 14 years of research and clinical development efforts and costs around 2 billion us dollars of 10 000 or more hits tested in early drug discovery only one may eventually lead to a drug that reaches the market [Music] in the late pre-clinical stage further experiments are conducted on the drug candidate to ensure it is safe for patients and has the required pharmacokinetic properties like appropriate absorption and metabolism by the human body these experiments are executed with extraordinary diligence to minimize any risks to human test subjects animals play a critical role in the drug discovery process as well although much research and development can be done using various experiments or using computers complex disease mechanisms can often only be understood through the use of animal studies also governments and regulatory authorities require that medicines be tested in animals before they are tested in humans novartis keeps this research as limited as possible and always ensures that animal research is scientifically acceptable according to current standards and regulations for these reasons novartis continues to use animals in its quest to find innovative safe and life-saving medicines for patients at the same time novartis is committed to refining reducing and replacing the use of animals in research and upholding the highest standards in animal welfare clinical trial programs consist of several phases each of which is focused on evaluating drug safety and effectiveness or efficacy information on ongoing clinical trials can be found at www.clinicaltrials.gov in phase one of clinical trials the drug is usually tested in healthy volunteers to determine its safety and pharmacokinetics in phase two the drug is given to a group of about 100 to 250 patients with the disease to evaluate its efficacy and to determine the optimal dose in addition the safety of the drug and its side effects are evaluated as these may be different in patients compared to the healthy volunteers tested in phase one novartis also conducts trials called proof of concept or poc trials which are often a mix of phase one and phase two studies a group of well-defined patients is treated with the drug candidate to provide an early indication whether it actually affects the target in the intended way or has a beneficial impact on the disease these studies allow novartis to rapidly invest resources on drug compounds which are effective and safe this way the appropriate medicines can reach the patients faster the data from phase 1 and phase 2 studies provide the scientific confidence necessary to continue the development of the compound in larger clinical trials [Music] in phase three of clinical trials 1 000 to three thousand or even more patients are recruited for research with the investigational drug phase three clinical trials are undertaken to confirm the effectiveness of the new drug monitor side effects compare it to established treatments and gather additional information to allow the drug to be used safely [Music] to bring a new medicine on the market every new drug needs to be registered by the health authority data from all clinical trials are collected and compiled into a document called registration dossier the registration.ca will include efficacy and safety data to support the final intended use of the drug the dossier is then customized for different regions and countries around the world to meet the requirements of health authorities this is a crucial step to ensure that patients all over the globe can access the innovative medicines that have made it through the complex drug discovery and development process once the registration dossier is approved and the product is launched several activities will continue like drug safety monitoring which is mandatory post authorization safety updates annual reports and any additional information required by the health authority must be provided at defined intervals as long as the drug remains on the market often phase 4 clinical trials are initiated to gather additional data not collected in the phase 3 program this may include efficacy safety additional benefit and risk information as well as pharmacoeconomic data our mission is to provide safe and effective treatments that benefit patients and improve the quality of their lives join medicinal chemist and in the pipeline blogger derek lowe as he reveals the seven steps and essential questions in drug discovery i'm going to give an overview of drug discovery so this takes us with everything all the way up to the clinic first one disease pathology this is a high level strategic question what therapeutic area do we work in what disease are we targeting the next step is target id that is more specific this is when we start saying what exact process are we going to target in this disease area now once you've done that your next step is assay development and screen the big question here is what kind of assay are you going to run do you have a specific molecular target in mind or are you going to run phenotypic looking for the desired effect in some organism model that takes us to the next step step four is hit to lead you've run your screen now you have the hits the idea is to triage these hits into the most interesting things that are possibly interesting and things which really just have to be pushed aside now that you narrow down you then go on to lead optimization traditionally lead up is classic medicinal chemistry this is really the part where everyone has to start improving the classic properties potency selectivity toxic side effects and pharmacokinetics a few months would be the shortest lead up that you can imagine and a few years is not unheard of either but once lead up has narrowed things down to just one two or three clinical candidates then you move on to pre-clinical development you've got the classic scale-up questions can this compound be scaled up at all what shape is the root in can the reagents be sourced is the yield and the purity profile reproducible you also have talks to worry about the standard is two week talks in at least two species usually one small one and one large one and finally that takes us into the clinic which is of course our goal the clinic is where the real money gets spent in this business everything that happened pre-clinical those are round-off errors compared to what you spend in the clinic that doesn't mean that earlier stuff isn't important that means it's critical that is the leverage point for the whole process if you don't get those things right you run a risk of wasting vast amounts of money and vast amounts of time in the clinic so all of these details before then have to be done well to the best of everyone's ability [Music] join us live every thursday at 2 p.m eastern for the best and brightest minds in chemistry so let's go now with drug development so we have this figure we have the in vitro study so in vitro study is usually the traditional research that you do in in our research so that is called an in vitro not identifying the chemical synthesis and it could be a possible lead compound we also have our animal testing you have our clinical testing and marketing so usually our in vitro studies ranges from zero to two years and our animal testing from two two years to four years and then when it is approved it could now be a new drug application which will be applied in the fda to be able to approve its clinical testing and to its marketing so let's go with our in vitro study so so in our in vitro study it is the a new chemical entity that has been discovered through either chemical synthesis organic synthesis or molecular modification or from isolation from plants which is we usually do in our research so after that it has been discovered it could be considered as a lead compound so when you say lead compound it is not a prototype it has a fundamental desired biologic or pharmacologic activity but it does not possess the following pitch feature the potency absorbability solubility and low toxicity because sorry because in individual study we just discussed are we just able to develop or to being able to see that if that plant or if that chemical has its potential for the specific effect so let's go now to the animal testing so it is called the pre-clinical studies so the goal of preclinical studies is to get information of the efficacy the toxicity and the pharmacokinetics of that drug so in toxicity we have our acute toxicity and we have our subacute and chronic toxicity which is to be identified so we also have types of animal tests so the pharmacologic profile is a description of all pharmacologic effects of a drug so we have for example the effects on cardiovascular function gastrointestinal activity respiration endocrine function and cns function and others so both are graded and quantile dose respond data are gathered so we have now the reproductive toxicity test so it involves the study of the fertility effects of the candidate drug in its teratogenic and mutagenic toxicity when we say teratogenesis it can be defined as the induction of developmental defects in the somatic tissues of the fetus for example the exposure of the fetus to a chemical infection or radiation so we have example of teratogenetic genesis so we have data little my drug iso39 fibroic acid ethanol glucocorticoids warfarin lithium and our androgen so teratogenesis is studied by treating pregnant female animals or usually do with mice or rabbits at least two species at selected times during early pregnancy so when organogenesis is known to take place by later examining the fetuses or neonates for abnormalities so another mutagenesis so it is defined as the induction of changes in the genetic material of animals of any age and therefore induction of heritable abnormalities so our aims test is the standard in in vitro tests for metagenicity it is it uses a special strain of salmonella bacteria that depends on specific nutrients in the culture medium so the loss of this dependence as a result of exposure to the test drug signals and a mutation so we also have our dominant lethal test it is an in vivo mutagenicity test carried out in mice so male animals are exposed to the test substance before mating so abnormalities in the results of subsequent mating such as loss of embryos and deformed fetuses signal a mutation in the male's germ cells so the fda has used five level descriptive scale to summarize information regarding the safety of drugs in pregnancy so for example we have our category a so category a has been tested with human studies or pregnant women and with our animal studies so the result for our category a is the drug is safe in all trimesters with pregnant woman so the category b is it does not have it was not tested with human studies but tested with animal studies so the result of this drug is safe in all trimesters so for category c it was tested with it has not been tested with human studies but has been tested with animal studies so the result for this is the drug is unsafe and can cause fetal harm so the drug should be given only when potential benefit justifies the potential risk to the fetus so our category d has been tested by both animals and humans so the result of this one is that the drug can cause fatal harm but the benefit of giving the drug to pregnant women may warrant its use despite potential risks so if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or ineffective so our category x which has been tested in both human and animal studies results in that the drug can cause fatal harm so this drug is contraindicated in women who are or may become pregnant this is our pregnancy drug category so i hope you will memorize this one so we also have our carcinogenesis so carcinogenesis is the induction of malignant characteristics in cells but difficult and very expensive to study so the aims test is often used to screen chemicals because there is a moderately high degree of correlation between our mutagenicity and carcinogenicity in some animals so these are the agents with no carcinogenic effects such as coal coal tar aflatoxin dimethyl nitrous amine and nitrous amine urethane vinyl chloride and polycyclic aromatic hydrocarbons in tobacco smoke and other tobacco products let's go now with our clinical trials the phase one phase two phase three and phase four clinical trials so with the phase one so the subject for our phase one clinical trials we have the they have to assess the drug to a healthy volunteer so usually there is 20 to 100 subjects without disease so the purpose of this is for safety and the data obtained is the pharmacokinetic and the pharmacodynamics of drug so we go to phase two so the drug is now tested with patients having disease so usually in phase two 100 to 200 subjects so the purpose of this one is to determine the efficacy and the data obtained is efficacy of the drug so in phase 3 it is given to several hundreds to several thousands of patients so we have one thousand to six thousand subjects so these are patients with disease so the purpose of this is for the safety effectivity and dosage so the data to be obtained is safety and effectivity of the drug so phase four now it is now given to thousands to millions so post marketing surveillance and for pharmaco vigilance so my question for you for now the kovid 19 vaccine no it has been declared now um it is already on its clinical trials so for you where do you think the phase three and the face the face of covenant in vaccine um now so what phase of cavity 19 vaccine is now they are doing so are there under phase one i think not phase two probably not so i believe phase three because they are now going to for example the russian but they are now going to countries for the philippines so they might be targeting a bigger number of people so probably the covered by 19 vaccine right now is already on its phase 3. let's just cross our fingers that it is it gives us a very safe and effective results for it in order now approved by the fda to move to phase four and to market the drug for us to use para mabalec so let's have our orphan drug so we say orphan drug it is a drug for rare disease so one affecting fewer than 200 000 people so the study of such agent has often been neglected because profits from sales of an effective agent for an uncommon ailment may not pay the cost of development so we don't see much of orphan drugs because as it is defined is only for rare diseases so usually having people with rare diseases are one out of um fewer or more than 200 people so of course in a business side they will not raise the the budget because it is very expensive when being studied so you will not raise a lot of big money for a very small um small profit so maybe rich people could afford this one so that's it for the drug development and regulation and that's it for our chapter one i know there are still topics that i i wasn't able to discuss so i already give to you now the time to study for the rest of the topic for our chapter one so please study ahead of time for