Practical Aspects in Early Drug Development - Research Paper Example

Patients, who are combating a fatal illness or managing a chronic state, live in hope of new medicines and enhanced therapies. These hopes are met with new medicines and treatments that improve health and offer patients better treatment options through drug innovation. Disease is a common enemy known to man. Medicines and therapies in development are giving patients and physicians new weapons in the war against diseases. Before a drug is introduced in a market, it undergoes four main stages: drug discovery, preclinical testing, clinical trials wherein the drug is tested on volunteers, and lastly, the drug review of authorized institutions. Extensive research and testing is conducted by scientists, whether from the government, academia or from the private sector during these stages in order to come up with safe and effective medicines. The entire procedure typically takes 15 years to be accomplished. It can then be concluded that drug development is complex and expensive, which require various chemical compounds for their potential to cure disease. Studies by experts show that there are several factors which now act as barriers to drug development. These factors were said by the experts as affecting the figure of drugs developed, the price and span of the medicine development procedure, as well as the types of medicines being produced. First, there is difficulty in translating research discoveries into safe and effective medicines because of limitations on scientific understanding. Second, drug developments are highly subjected to the decisions made by the pharmaceutical industry, third, there is a growing hesitation concerning regulatory standards for determining whether a drug should be permitted, lastly, there are now problems to the growing inefficiency in protecting intellectual properties. There are suggestions offered by these experts in order to address these pressing issues. One is to boost the number of scientists who can interpret drug discoveries into efficient new drugs. This can be obtained through further training. Another suggestion is that there should be provisional consent for allowing certain drugs based on shorter clinical trials by means of less number of patients. The medicine development procedure over the last ten decades has become a greatly advanced process with distinct sequential phases. The first stage is the drug discovery. This refers to the process wherein scientists or researchers from pharmaceutical companies, academia, and government look for and recognize chemical entities which shows potential, or compounds, which are capable of curing or treating diseases. As its name suggests, the aim of this stage is to look for a new molecule or a new chemical entity (NCE) which have probability to be made as an efficient drug (Spinasanta, 1). The first move in this phase is to decide what therapeutic fields are possible to be worth the requisite investment for a new drug development. This step is not as simple as it seems, the choice will very much have an effect on the feasibility of the pharmaceutical company creating it. Drug development involves a large amount of money, which is at stake. For one, in developing a new drug it will involve a great amount of money. For example, in the United States, approximately 500 million dollars is needed for one to be able to bring to the market a new medicine. Another point is that these drugs when successful, largely contributes to the financial state of the company. Using simple logic, if the drug is unsuccessful, the company will never get back the cost of the new medicine they developed. And in the extreme, if it is found with very problematic side effects or, liability problems, it can put the company in a bad position. One of the aims of the chronological phases of drug development is to detect such liabilities. From there, the company can decide whether to continue the project and invest more money or altogether kill the development of the drug, but this still depends on the severity of the problems. What are the considerations in developing a new drug in a certain therapeutic area? One of the most important considerations is the size of the market. This is one of the determinants of how much profit the new medicine will produce. For example, if a pharmaceutical company in Singapore, a very small country in Asia considers the idea of introducing a new drug in the domestic market, they will first study of the size of their market will support their goal of generating profits. Another important thing that they must consider is the competition in their area. That company in Singapore may also decide against the idea of making new medicine which they know that their competitors have exclusive rights. The situation which is most favourable for a company is when all of the existing drugs have either gone off its exclusive rights or will soon go towards that road. Under such conditions, there will then be generic competition, but the drug will not be counter-detailed by a competitor. The condition or the disease that the future product will target should be explored in detail. The percentage of the population that suffers from that certain disease should be surveyed as well as those who are seeking treatments (Schacter, 6). Their clinical needs should also be checked, if these needs are met by current clinical treatments. Other important considerations include the degree difficulty in making the product and the likelihood of the product to be permitted by the regulatory board (Schacter, 5) . The second stage of drug development procedure is the preclinical phase. This takes place before the clinical trials. In this stage the, the drug is tested in the laboratory and on animals so that a plan is made on how trials will be conducted on humans. This is needed in order to test whether the drug is safe enough to be tested on people, or that the proposed clinical trials are safe (Schacter, 5). If this stage demonstrates safety for human volunteers, then sponsors can now move on to the third stage of drug development. Before starting the clinical trials, which is the third stage of drug development, a standard procedure is for the pharmaceutical company to file an investigational new drug (IND) application to the regulatory bodies concerned. The IND is a documentation of the procedures and controls of the upcoming clinical trials which must state a fact that the planned procedures are there to minimize the risk to human volunteers during the trial and people as a whole. It also contains the responsibility of the institutions and individual concerned to carry out the trials which must conform to regulations (Schacter, 2). A formal approval will not be issued by the food and regulatory agencies if there are issues such as if it determines that the volunteers will be exposed to an unreasonable and major risk of illness and harm (Schacter, 2). If there are no objections from these agencies, shipping of the approved drug will be permitted to cross state lines for human consumption. In order to ensure safety, clinical studies are controlled carefully, these studies follow a meticulous, predetermined research plan, following extensive consultation with the food and regulatory agencies. Before moving on the next stage of drug development, it is important review first research ethics. The Nuremberg code is a code of ethical principle which was formulated by a group of doctors and judges. This code provided the protection of human subjects of research. First, the code acknowledges the different relationship that is between a researcher and his/her subject. In the Nuremberg Code, the voluntary approval of the human subject is absolutely important. This person involved, upon giving his/her consent should be in a legal capacity to give the consent (Schacter, 86). Aside from that, the person should be in a situation where he/she is armed with free control to choose, this means that there is an absence of force, fraud, deceit, duress, overreaching, or other concealed form of restraint or coercion. It is also proper that the volunteers be appropriated with sufficient knowledge, regarding the study or tests which will involve them (Schacter, 87). The knowledge mentioned above should involve the nature of the study, duration, and of course its purpose of the experiment, the methods and kind of tests that will be performed and the risks and inconveniences expected. This will ensure that their decision to give their assent will not be based on ignorance about the matter. Second, the experiment should be done to produce results that is helpful for the entire society, and it should not just be another study, not random, and of course not unnecessary. Third, the experiment should be planned based on the results of the preclinical trials made with animals (Schacter, 88). Fourth, the planned method or the experiment as a whole should be carefully checked so as to eradicate unnecessary physical and mental pain and injury. Fifth, the experiment should be armed with the proper facilities which are needed to protect the participants from possibilities of injury, disability or death. Another important consideration is to let only a person who is scientifically qualified to conduct the experiment. Lastly, the participant should be informed that he or she can end the test if he/she has reached the point where continuing seems impossible. On the side of the researchers, they must be prepared to end the experiment at any stage if what he is happening is already against his proper judgement as an expert (Schachter, 88). Clinical trials are carried out in order to investigate and test the potential of a certain product as a new medicine. Ideally, the potential drug is compared to a placebo, which is something with no effect. In other times, the effect of the potential drugs is compared to medicines which are already used by people. The placebo will be made to look like the medicine being tested, a pink tablet, a blue tablet, a coloured liquid or a colourless one. As a matter of fact, the patients, or the volunteers do not know if they are taking the placebo or the tested drugs and even the researchers themselves do not know it sometimes, or to be more precise, most of the time. This procedure is done in order to remove the effect of the patients and researchers’ personal opinion from the results. Researching on potential medicine involves three phases; these three phases are different from each other. Phase I. Ideally, this phase involve healthy volunteers. The goal is to focus on how safe the drug is and how it interacts with the body. An example of which is to see the effect of different doses to the concentration and duration of the tested drugs in the human blood. This trial will give the researchers an idea of whether the drug exaggerates the effects of other medicines that might be taken at the same time. Ideally, the safety studies are tested on 20 to 100 healthy volunteers and potential side effects are uncovered at this stage. In short, safety issues are studies broadly before testing it to those who have the certain disease or condition. Phase II studies the effect of the potential drugs on 100 to 500 patients who have the targeted disease. The importance of this phase is the information it gives if whether the potential drug is efficient and effective in treating the disease and what is the proper dosage which is the most promising (Spinasanta,1). At rare times, this phase also allows the researchers to see if it has an effect on other illnesses. Phase III establishes efficacy and safety more accurately which is important to its approval by regulatory agencies. The drug, at this phase, is tested on 1000 to 5000 volunteers. The tests in phase III are designed to establish the safety and efficacy of the drug in a large and diverse population. The average time this three phases consumes is 7 years. Phase IV is the final stage wherein the concerned regulatory bodies are going to review the drug and to decide whether they will approve it or not. At this point the regulatory bodies will check the drug if it really meets the standards of the regulatory agency (Spinasanta, 1). This stage is also called the post-marketing study period where marginal information are outlined regarding the drug’s risks, benefits, and optimal use. The thalidomide tragedy which occurred in the 1960’s triggered the concerned agencies to tighten regulations concerning drug development. This tragedy involves babies who were born with major physical and mental deformities because of the lack of studies conducted to identify such side effects. This medicine entered the market as treatment of lesions associated with erythema nodosum leprosum. If taken by pregnant women, the baby will be greatly affected through malformations. Why do we test potential new medicines in healthy volunteers? If testing new medicines in healthy volunteers is such a good idea, why do we sometimes not do it? We must recall that in phase I of clinical trials, the potential drugs is tested in healthy volunteers, take for an example the case of biotechnology treatments. The dilemma in this case is the potential risk of the potential drug on healthy patients or to the volunteers. Nonetheless, it is important to do so, so that the researchers can learn about its effect on healthy volunteers if there is/are any. One of the advantages of testing the drug to healthy volunteers is the number of available health volunteers, unlike when you test the medicine to those people having the disease you are targeting; it is relatively far simpler (Spinasanta, 1). These healthy volunteers are also more tolerable of rigorous test procedure unlike those who have the disease, one because of the fact that they are not sick, and second, they have the time in the world to do so, compared to someone who is terminally sick. Another edge of health patients is that the results of the trial with them as volunteers will help the researchers determine the effects of the potential drug without the interference of a disease and other recent treatment process which could influence the absorption of the drug into the volunteer’s system. At rare times, testing a potential drug to healthy volunteer is a safer path to travel than the sick ones. For example, if the drug being tested is an antiarrythmic drug for ventriculartachycardia, testing this drug to volunteers who have heart failures because these kinds of patients will most probably have multi-organ diseases. The problem lies on the absence of knowledge to how such diseases will react with the potential drug. These are just some of the factors which affect the researchers’ decision of testing the drug preferably to healthy volunteers. The criteria in healthy volunteer selection include the age. Researchers prefer those whose age are ranging from 16-65 years old, but of course there is an exemption if the drug is specifically developed for babies, toddlers or young children, or if it targets very old people. They also consider sex, specifically pregnant females and they do not choose those who have allergic reactions to anti-biotics. Those who are chain smokers and heavy drinkers who consume a large amount of alcohol are also sometimes rejected because of its effect on the volunteer’s liver which may affect the result of the tested drug. Lastly, in choosing volunteers, they check them if they have HIV, HBV, HBC, and if they have it, they are excused from the list. Clinical studies will help researchers identify about the actions of the potential drug among different characteristics in people such as age, gender and genetic polymorphism. Drug development in a certain country follows standards which a little bit modified in every country. These guidelines are strictly established by the regulatory agencies in order to minimize major mistakes that can take place. Explain what is meant by a crossover and a parallel-group study. Discuss the strengths and weaknesses of each type and discuss (with examples) when each design might be preferred over the other. The parallel group study is a gold standard trial design, as well as the crossover study group, in drug development. A parallel trial involves the make use of two or more studied groups at the same time. Each group takes one of the possible treatments or consumes one of the possible doses. This kind of trial is used in almost all conditions in which the disease’s condition is comparatively short term, potentially remediable or fatal. Parallel studies are straightforward, more forceful and more rapid than crossover studies and almost certainly can reduce study duration for each individual subject while concurrently escalating population contact with clean and safe data (Simpson, 2). Its strengths include its better ability to address cases where it involves long treatment periods which, for example, requires more than three months. It is also better suitable if the trial is comparing more than three treatments. But unlike crossover designs, this kind of design requires more participants in the study, but is shorter in duration and easier to analyze the statistical data. The crossover study design is used when one focuses on the effect of the different dose levels or more broadly the effect of different treatments on volunteers, the unpredictability of the responses of the different participants can overpower any treatment differences (Simpson, 2). From the facts stated above, crossover design then, is appealing because it involves people who will get one of each drug, the potential and the existing one, or each dose level (Simpson, 2). It is designed to balance out any period effects because the order in which the participants receive the drug may have an effect. The carryover effect happens when the drug’s effect carries over to the next period, and this is the main weakness of this design (Simpson, 2). Theoretically, the strength of this kind of study is very appealing because of its ability to sense even the slightest differences with comparatively much lesser sample sizes. The most horrible likelihood in this design however, is that the data collected may be nearly useless. Mostly, even with only a two-armed study (two dose levels or two drugs), dropouts will occur. Then, we can conclude that the effect is no longer even-handed, and the first period can only be analyzed. Thus, its design is no longer effective. Many of these designs confound carry over and period effects. It may be then unfeasible to sense the treatment effects for which the study was intended if physiologic or psych logic carryover occurs (Simpson, 2). A crossover design is formally defined as a design where a participant receives two or additional treatments in a random order in dissimilar periods (Simpson, 2). It allows the study of differences amid treatments and sub sequences of treatments. Crossover design is typically used when studying constant circumstances which are not likely to change over the stage. One of its attractions is the design’s small sample requisite. One of its major problems is the carryover of the medication itself or the physiologic or psychological effects. If this design is chosen for clinical trials, then it must be adjusted for the effect so as not to confuse it with the period and treatment effects. We can then conclude that a crossover study is less often used than parallel study because of the difficulties of showing the effect that carry-over into the next stage of the trial. It is also a known fact that this sort of design is very susceptible during the washout period because the disease is recurring every time to the pre-treatment state. Let us now summarize the benefits of the parallel design and crossover designs: The parallel trial is important and is more appropriate when dealing with short term diseases, and also to conditions which can be treated by treatments and also to conditions which are fatal. Second, this is more preferred by researchers which are targeting conditions which are recurring, in other words, chronic diseases. Third, it is also more appropriate to use this design if the treatment periods last for more than three months and when the target of the study is to compare three or more treatments. It is preferred because of the fact that is easier to use but then it requires more patients for the study, however these patients are exposed to minimal risks. These are also shorter, in terms of the duration of the trials (Simpson, 6). On the other hand, cross over trials have the edge against parallel trials when it comes to the requisite of volunteers. Crossover design requires lesser volunteers. But then the problem lies in the difficulty of execution and the parents will tend to suffer from withdrawals after the trial’s duration. Overall, it will take more time to execute this kind of trials, and the analysis needs more effort because it is normally harder than the parallel design (Simpson, 5). What is meant by ‘polymorphism of drug metabolism’? With respect to such polymorphism, explain what is meant by genotype and phenotype. Why does polymorphism of drug metabolism matter? This part of the paper is the analysis of polymorphism of drug metabolism. But in order for us to do so, we should first define the two concepts separately and then analyze their relation after. Polymorphism is a general series difference experiential in person at a polymorphic site. It employs nucleotide substitutions, insertions, deletions and micro satellites. On the other hand, drug metabolism is the biochemical modification f drugs, often through specialized enzymes. Enzymes are defined as many proteins created by the human body that is capable of accelerating the metabolic processes of an organism. Moving on, drug metabolism works to convert lipophilic chemical compounds into without difficulty excreted polar products. Thus, drug metabolism can stake the result in toxification or detoxification, the commencement or not of the chemical compound. Xenobiotics or organic chemicals are metabolized by the same enzymes. Genetic polymorphism is defined as the occurrence collectively in the similar position of two or more irregular forms of a species in such magnitude that the rarest of them cannot be maintained just by persistent transformation. For this particular topic, we can also define genetic polymorphism as the monogenic variations that are present in normal individuals. Therefore, drugs can be successful treatment for a certain group of people but then have unfavourable effects on another group. Genes play a vital role in the stake of drug’s inefficiency or inefficiency. Specifically, the different effects can be partly explained by the genetic codes for pharmacokinetic and pharmacodynamic which are not the same for individuals. There are different drug effects because of receptors or drug metabolizing enzymes. A main foundation of variable metabolism and linked events is the genetic polymorphism of drug metabolism. One way of showing these differences is through observing differences between people through their drug metabolism and subsequently in drug kinetics and answer shows that genetic differences among unlike ethnic groups could affect the drug metabolism. Genotype is the code where one can find the information inherited from both parents, this information exists in all living things. The importance of this instruction lies in its need of maintaining the lives of living things. The instructions are embedded in a coded language which is called the genetic code and are used by all cells. Inheriting traits happen when these instructions are imitated and then passed from parents to off springs. Moreover, genotype also controls many things such as the production of protein macromolecules and the management of metabolism and synthesis for plants. On the other side of the coin, one can find the phenotype. This is what you see when you look at a living organism, from head to foot, to internal organs which can also be seen during surgeries. In short, everything than can be possibly seen is a phenotype, it is the summation of atoms, molecules, macromolecules, cells, tissues, organs etc. It involves everything which can be observed whether if its structures, function or behaviour of a living things. Genotype can be known through DNA level, and the study is called pharmacokinetics, phenotype on the other hand can be studied b using superior methods for metabolic uncovering or through clinical investigations. Measuring these two concepts is useful in determining the choice and best dose of drugs in the clinical trials. What is the QT interval on the ECG,and how is it measured ?Why have some drugs that prolong QT interval been withdrawn from the market? The QT interval on the ECG indicates the duration for both ventricular depolarization and subsequent depolarization to take place and consequently estimates potentially the extent of a normal ventricular stroke (Klabunde, 1). The electrical action that gearshift the contraction of the heart’s cells is mirrored on this QT interval. The range of this interval is between 0.2 to .04 seconds which further depends upon the heart rate. It depends on the heart rate because it affects the QT interval greatly. If the heart rate is high, ventricular action potential takes a shorter time, and this will then decrease the QT interval. The normal QT interval is important to be knowledgeable of so that one can calculate the pathological signs of the QT interval. In calculating the normal QT interval, one should divide the QT interval by the square root of the preceding R-R interval which is the interval between ventricular depolarization (Goldenberg, 10). An unpleasant result of a number of drugs is their capability to holdup cardiac polarization. This is a result which can be calculated as continuation of the Qt interval on the electrocardiogram. This delay in the cardiac polarization paves the way for the development of cardiac arrhythmias, where in one of the most familiar is the Torsades de pointes. This form of ventricular tachycardia is a polymorphic tachyarrhythmia that appears on the ECG as progressing winding of the QRS complex around the isoelectric baseline (Goldman, 10). Torsades de pointes can degenerate into ventricular fibrillation and the result of this may be unexpected passing away which is as widespread in women as to those in men. There is also an effect of the age and gender when it comes to the QT interval. The QT interval is reported and proved to increase as the bradycardia increases, a positive correlation, and it also decreases as tachycardia decreases, a negative correlation. It is also proven that men’s QT interval which is 0.39 seconds, is shorter than that of the women’s, which is said to be 0.41 seconds. QT interval is also affected by exogenous variables such as electrolyte balance, drugs, and ischemia. It is also now an issue that these kinds of drugs can modify genetic appearance mutations and the genetic polymorphism in that drugs, and drug relations for example ketoconazal with terfenadine (Goldman, 12). Prolonging the QT interval encompasses a large percentage of drugs which is associated with it. It also increases probability of drug-induce ventricular tachycardia. The authorities are already exerting effort in order to remove this in the market. One of the side effects of this drug is the presence of drugs that inhibits KCNH2-encoded potassium channel. It is also an ongoing campaign that drug prescription should include that calculation of risks and benefits which is known to prolong QT interval. Describe how the beneficial effects of an anti-asthmatic drug may be measured. Asthma is an unceasing lung disease which inflames the airways (Szetfel, 1). Moreover, this condition is an ordinary reversible airflow which is a barrier in the airways that responds to specific stimuli, and it also occurs when the bronchi is inflamed. When asthma attacks, it makes the airways swollen, and when they answer to certain stimulus, the airways become abnormally narrow along with the tightening of the muscles around them. There are some corrections about the myths on asthma. First, asthma is not all in the mind. It is not a psychological defect, but strong emotions do trigger attacks sometimes. Second, it is not true that one can outgrow asthma. Most of children who have asthma and outgrow it during their teenage years do not actually lose it; the absence of the attacks can only be explained by saying that it has become inactive (Szeftel, 1). Third, there are no cure for asthma, the most one can do is to manage the condition through medical care. This should be taken seriously since it can cause death. In the USA alone, there are about 5,000 deaths which are caused by asthma and 500 in the Canada, annually (Szeftel, 3). There are two kinds of asthma, one is chronic asthma and the other is acute. Symptoms include cough, shortness of breath, tightening of the chest, and breathlessness. Chronic asthma, although manageable, is very hard to manage (Szeftel, 2). It can be deadly and those who are suffering from this kind of condition needs to undergo immediate treatment. Treatments include Anti-asthmatic drugs, which includes bronchodilators and anti-inflammatory agents. According to studies conducted in order to evaluate potential medicines for asthma, it was found out that many cells and mediators have an important role in the pathogenesis of asthma (Szeftel, 2). Beneficial effects of anti-asthmatic drugs through tests can be measure accordingly. One tool used is Spirometry, it works through assessing the severity of the airway hindrance and to monitor the whole treatment. Benefits can also be checked through blood tests (Johns, 21). It measures the antibody levels which were produced as a response to allergens or certain stimuli. Exhaled nitric oxide (ENO) level in individuals can also be linked with supplementary measures of inflammation in asthma. It was proposed before that this can act as a surrogate marker in asthma and can be useful in the measurement of the benefits of newly developed asthma medicines’ benefits (Johns, 21). Number of words: 4991 References Charlesworth B & D. 1979. The evolutionary genetics of sexual systems in flowering plants. Proc Royal Soc B 205, 513-30. Schacter, Bernice Z. ‘The new medicines’. Retieved from http://books.google.com.ph/books?id=SOwjeJ484bEC Grant, Peter R. 1999. Ecology and evolution of Darwin's finches. Princeton NJ. (see plate 7) Goldenberg, Ilan. ‘QT interval: How to measure it and what is 'normal'’. 27 March 2006. Retrieved from http://www.medscape.com/viewarticle/525633 Johns, David. ‘The measurement and interpretation of ventilatory function in clinical practice’. 2004. McGraw Hill: Australia. Klabunde, Richard E. ‘Cardiovascular physiology concepts’. Retrieved from http://www.cvphysiology.com/Arrhythmias/A009.htm Simpson, Pippa. ‘Cross crossover studies off your list.’ 18 October 2004. Retrieved from http://209.85.173.104/search?q=cache:9ZKGm1AZX0J:ssc.utexas.edu/docs/sashelp/sugi/24/Posers/p221-24.pdf Spinasanta, Susan. ‘New drug development’. 26 September 2005. retrieved from http://www.spineuniverse.com/displayarticle.php/article1343.html Sharpe, R. ‘The cruel deception: The use of animals in medical research’.1988. Thorsons Publishing Group, Wellingborough, England, pp. 105-6. Szeftel, Alan. ‘Myths, facts, and statistics about asthma’. Retrieved from http://www.medicinenet.com/asthma/article.htm Read More