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Over the past century, medical research on pharmaceuticals has greatly altered the organization of health care from mainly a painkilling practice to more of a science-based enterprise. During this time, advances in pharmaceuticals and sanitation have increased the average life-expectancy United States from 47 years to more than 77 years today. Not only are pharmaceuticals increasing the life-expectancy, but they are also improving the lives of millions of people by making them healthier and happier. The development of pharmaceuticals has relegated numerous infectious plagues of the past. They have transformed the misconception of the shame and fear surrounding a mental illness into a disease that is highly treatable with the proper care. Advancements have also assisted in the creation of dynamic independence for old age, rather than viewing it as a disability. Newer drugs have also made substantial progress in the fight against tough diseases, such as cancer, stroke, heart disease, and many other infections that were once thought of as an inevitable death. As the 21st century continues, these advancements in pharmaceuticals will continue to progress and develop. Pharmaceutical companies will continue to battle against civilization's ancient adversaries and will strive to conquer new challenges, which may include finding improved treatments and therapies for patients with HIV and Alzheimer's disease (History of Pharmaceuticals, 2008).
In order for medical researchers and pharmaceutical companies to make exceptional strides in treatments and/or therapies, they must follow through with the drug discovery process in which newer drugs are discovered or designed. Most drugs are discovered by either recognizing the active ingredient from conventional treatments or through unexpected innovation. The most important step is finding out how a disease or infection is controlled at the molecular and/or physiological level. Through this recognition, specific proteins can be targeted and the appropriate treatment can be prepared. The drug discovery process is a complicated progression that involves recognizing and validating the drug target, assay development, identification of the lead compound, lead optimization, and classification of a drug candidate for therapeutic efficacy. Once the drug compound has been properly identified and its assessment shows significant progress in these tests, the development of drug discovery begins (Drug Discovery, 2007).
Regardless of the advances in technology and biological systems, the drug discovery process is an extremely long-lasting, costly, complicated, and inefficient process with a low overall success rate. These all play a major role in the pricing and cost of pharmaceuticals. The success of the human genome project paved the way for the discovery of new drugs. By knowing the appropriate sequence and what it may encode, this allows researchers to save a substantial amount of time by eliminating the therapeutic agents that would have naturally been targeted. Unfortunately, it has been shown that newer targets are more likely to be unsuccessful than the more established ones. Due to the high failure rate with the newer pharmaceutical drugs (approximately 99%) many people question whether or not the benefits of these drugs are worth the overall expenditure. This is a question that will be answered throughout the remainder of this paper (Drug Discovery, 2007).
Food and Drug Administration
The Food and Drug Administration, or FDA, is responsible for the assertion and guarantee that food, cosmetics, pharmaceuticals, and medical devices are all extremely safe and efficient for its proper use. In order to effectively perform these observational safety protocols, the FDA is accountable for monitoring over a trillion dollars worth of commercial products. According to recent statistics that figure turns out to be approximately twenty-five cents of every dollar that American's spend on these products. It is extremely imperative that the FDA provide some sort of stability with the effectiveness and safety of each product. The FDA is able to perform these safety protocols through the assessment of the efficiency of controlled clinical trials and by studying the effectiveness from genuine use in an unrestrained environment. The FDA also places a heavy focus on the safety and efficacy for prescription medications and over-the-counter drugs before the pharmaceutical can be approved for marketing (Lipsky & Sharp, 2001).
The advancement in the regulation of drugs transpired as the direct result of a disaster, catastrophe, and calamity. Before the 19th century, everything and everyone associated with pharmaceuticals was fraudulent, demoralized, and crooked. Mayhem occurred because there was not any control over the marketing and manufacturing of pharmaceuticals. There were numerous complaints concerning the contaminated and unhygienic conditions in the meat-packing plants. There were also many implications of worthless and/or dangerous medications being marketed. These implications led to the development of the Food and Drug Administration Act of 1906. This law was the first to create standards concerning food products and drugs. The Food and Drug Administration act of 1906 contained three provisions: that it is mandatory that all pharmaceuticals reach an authorized standard of both potency and purity, it provided the proper definitions of adulterated and misbranded, and it also disallowed the sale and shipment of both misbranded and adulterated food, beverages, and pharmaceuticals (U.S. Food and Drug Administration, 2009).
Unfortunately, the Food and Drug Administration Act of 1906 was not very successful in preventing the inadvertent deaths of 107 people in 1937 from an approved drug, elixir sulfanilamide. These unfortunate events led to the Federal Food, Drug, and Cosmetic Act of 1938 that required manufacturer's to test for and demonstrate the safety of the drug before the sale and marketing tactics could take place. The FDA then began to issue trade correspondences to the specific industry concerning not only the appropriate labeling, but also the proper dispensing of drugs. These notices had specifications that required all drugs to either have a label with sufficient information for patient use, or a caution label that provided a warning to consumers that the drug should only be used if prescribed by a physician. Unfortunately, it was the manufacturer who made the decision on whether or not to place a caution label on the product. These trade correspondences were the first signs of the FDA's goal to characterize specific medications that should only be available through the physician as a prescription (U.S. Food and Drug Administration, 2009).
In 1962, manufacturers were required to provide the FDA with the appropriate safety information and also provide them with experimental evidence that the drug product was indeed effective for the associated disease on the label. During the late 1970's, apprehension over the overall quality of experimental data led to the FDA establishing guidelines concerning good laboratory practices for clinical trials. The main intention of these guidelines were to increase the overall assurance that the quality and validity of the experimental data submitted to the FDA was both precise and accurate. Most of these guidelines brought forth in the late 1970's are now a regulation, such as the need to grant approval, provide the crucial essentials of informed consent, and successfully provide the requirements necessary for institutional review boards, or IRBs (U.S. Food and Drug Administration, 2009).
The FDA has given their stamp of approval on more than 500 new prescription pharmaceuticals since the year 1999. With such a large number of new pharmaceuticals coming into the market every single year, it can be quite difficult for physicians to gain knowledge of the required information about each new product. Medical doctors not only do not have the time available to educate themselves about the new products, but they also are unaware of the process of drug discovery and the new market approval development. It is essential that physicians be well-educated on the products for which they are prescribing. By acquiring the knowledge about how and why clinical trials are being conducted, it can be extremely beneficial to their patients when being prescribed a new medication for their ailments. The comprehension of clinical trials increases the physician's ability to assess the risks involved in prescribing newer medications. This type of information is also significant because the physicians are well-aware of how the safety and effectiveness of the new drug is determined. Oftentimes, physicians dispute the cost of the newer pharmaceuticals because they are oblivious to the amount of time, money, and obstacles that are associated with bringing a new drug to the market that has just been approved by the FDA (Lipsky & Sharp, 2001).
Key Factors in Drug Development
It is imperative to first understand the basic functional process of the body, not only the normal functions, but also the atypical functions. The comprehension of these basic processes gives medical researchers a potential target by figuring out how the new drug could be used to avert, cure, and treat an improbable disease and/or medical condition. Occasionally, the medical researcher will find the correct chemical compound quickly. However, oftentimes hundreds or even thousands of compounds have to be screened to determine their effectiveness. This screening process requires performing many test tube experiments, referred to as assays. Assays are used for testing and assessing the activity of a drug in an organism and/or natural sample. Assays for possible drug development involve the target chemical compounds, which are added individually to enzymes, cell cultures, and/or cellular substances. The main goal of assays is to figure out which individual addition shows a positive effect. This can be an incredibly tedious process due to the fact that a large number of compounds may not show any positive effects. However, these assays will show the compounds that may point toward certain ways of altering the chemical structure of the compound in hopes of advancing its overall medical performance. These alterations in the chemical compound can be extremely helpful in the discovery a new drug (Drug Discovery, 2007).
From time to time, the origination of a disease is not known or identified through extensive research and analysis. By not knowing the etiology of the specific disease it is extremely complicated to identify ways in which the disease can be prevented and/or discovering a treatment worthy of approval. Given the unfortunate odds, cures of this nature do happen ever-so-often through attentive and innovative medical research and/or from an unforeseen finding (Junge, 2009).
A major advancement in the discovery of the first pharmaceuticals was discovered by the unsystematic testing of higher plants. Traditional medicine using plants and their extracts have been used for many years, and is still of great importance today in the drug discovery process. These chemical compounds can often be found in nature because they are produced by a living organism. These chemical compounds can arise from natural products such as fungi, viruses, and molds. Medical researchers are able to grow these individually in fermentation broth. Oftentimes, hundreds of thousands broths are used to test the efficiency and effectiveness of the compound that is made by the microorganism. They almost always possess useful characteristics associated with pharmaceuticals and/or some sort of biological activity which will be extremely useful in the development of these drugs. It is also apparent that the sheer quantity of these natural products makes them easily accessible for pharmacological research (Nevalainen, 2009).
Occasionally these natural products are successful without making alterations to their unique chemical structures. However, researchers are always continually searching for ways to increase the progress of the overall biological activity and curative properties of these drugs. They have figured that one way to make the necessary advancements in these natural products is to modify their original chemical structure. These modifications can be relatively simple or extremely difficult given the chemical structure and the alterations that need to be made. One simple alteration that was made by researchers to increase the solubility of water of that drug involved the formation of a phosphate ester bond in the hydrocortisone compound. Another minor change occurred in the class of antibiotics. This involved replacing the amino acid side chains in both penicillin and cephalosporin to increase their overall effectiveness against bacterial invasions. It is apparent that minor modifications like these can increase the drug's effectiveness and its ability to increase the overall drug resistance to harmful infections (Drug Discovery, 2007).
Along with minor modifications, it is also significant to know which part of the herbal product is responsible for the bioactive properties of the drug, also known as the essential structural unit. By knowing the essential structural unit, organic chemists are able to synthesize a great number of new compounds almost every single day. For this reason, organic chemists are essential in the pharmaceutical industry. Another benefit of having organic chemists involved in the pharmaceutical process is that they have the background knowledge of the necessary theoretical considerations, therapeutic chemistry, and biological and chemical mechanisms. It is because of these mechanisms that there is a more balanced approach into discovering new drugs. Even if these mechanisms do not produce new drugs, the extensive level of research performed on these bioactive processes may disclose an unforeseen action for an individual compound. These unanticipated findings are beneficial in that they can lead to a new biological idea, a new series of chemical compounds, or another successful drug. Organic chemists are also responsible for advancing the pharmacologic properties by manufacturing identical characteristic compounds that play a role in the biological activity of the product. A prime example of this type of behavior would be the detection of the local anesthetic agent from cocaine through the local blockage of the conduction of the nerves (Nevalainen, 2009).
Even if the biological mechanism and hypothetical considerations are known, it is still a tedious process because there is no certainty that the balanced approach will be effective. Therefore, chance and fate have a lot to do with the discovery of drugs. On the other hand, by knowing these basic biological pathways, this might point towards a certain chemical intermediaries, such as an enzymatic catalyst or primary receptor, which may play a major role in the unhealthy medical condition. With the advancements in technology, computers can be used to help design possible drug candidates if the enzymatic proteins and primary receptors are known. These computers possess a controlled specialty system that is able to rapidly locate thousands of enzymatic or receptor-sites on chemical compounds. It is important to know the enzymatic positioning because it is the catalyst that affixes itself to the proper site on the membrane of a cell. This attachment is extremely imperative because it is the origin of the medical condition. Technological advancements can help replicate the structure of a chemical compound in hopes of designing a new chemical structure that would combat the original structure. This computerized structure will allow researchers to visualize the site of the receptor. This visualization is essential in the formulation of a chemical compound that would act as a barrier to that specific enzyme, therefore blocking the possible detrimental attachment. Computerized structures are extremely helpful, but are not a definitive solution (Richards, 1994).
Drug Discovery Process
The pharmaceutical discovery process is a progression that applies to drugs, products, and protocols which will be used in humans. It is a very complicated, time-consuming, and costly process that involves numerous chemical compounds that must be manufactured and tested in hopes that one compound will attain an enviable result. The drug discovery process is divided into four different phases. The first phase is called the preclinical phase, which takes approximately 3 to 4 years for completion. If the chemical compound surpasses the preclinical stage, an investigational new drug, or IND application must be submitted to the FDA. If the IND is approved, the chemical compound will be examined further in Phase I, II, III, and IV clinical trials. These clinical trials can take approximately 5 to 6 years to successfully complete. During the whole clinical trial process, the medical researchers are constantly communicating with the FDA in hopes of continuously monitoring all safety issues. When all phases of the clinical trials have been completed, the manufacturer then submits a new drug application, or NDA to the FDA. The FDA will review this NDA and has the authority to either approve or deny the application. Frequently, the FDA will submit a request that the researchers provide more experimental evidence that the drug is indeed effective before making a definite decision. If the request is affirmed, they can also propose that the manufacturer perform further post-marketing research. The FDA approximates that it takes somewhere between 8 to 12 years to study and develop a new drug before it can even be considered for approval. The 8 to 12 year approximation takes into consideration the premature laboratory and animal testing, along with the clinical trials that involve human subjects (The Drug Development and Approval Process, 2009).
The development of pharmaceuticals can take place through a variety of different ways. Therefore, it is not a surprise that most chemical compounds have a difficult time getting approval from preclinical testing to the market. A rough estimate of the approval rate of a successful drug affirms that for every 5,000 to 10,000 compounds that go through the preclinical testing phase, only one drug will be approved for the market. Those are extremely tough odds for the amount of time and money spent on research and development. In the early 1990's, the Congressional Office of Technology Assessment provided an assessment of the amount of money it costs to develop a new drug product. This assessment approximated that the cost was $359 million. Nowadays, the cost to develop a new drug product is closer to $800 million (Schweitzer, 2007, p. 34).
The drug development process begins with the preclinical phase. This phase takes advantage of the major progression in the comprehension of a disease, the pharmacodynamics associated with these drugs, the technology used, and overall chemical structure. These advances are all important because they can be used to break down an illness or a disease into specific components that may benefit researchers by providing them with ideas for targeting the development of a drug. As it was mentioned earlier, if a researcher determined that a catalyst was a major component of a disease, they might aim to inhibit that specific catalyst (Olejniczak, Gunzel, & Bass, 2001).
The improvement in the field of fundamental science has helped researchers accurately establish the active enzyme site. This information helps the researcher to better synthesize and test each compound. After a lead compound has been determined, it has to be tested in live animals. These animals are usually small rodents, such as mice, rats, or rabbits. It is a requirement of the FDA that the proposed drug be tested on animals before a human being is introduced to a new chemical compound. Animal studies use in vivo experiments to determine the overall safety of the future drug. These experimental tests intend to establish that the proposed drug does not cause chromosomal abnormalities nor does it cause dose-dependent toxicity at levels proven to be effective. These resulting data associated with these tests are then recorded and filed with the FDA in the IND application. The IND also possesses pertinent information on the chemical and manufacturing data, the results of the studies performed on animals, the pharmacokinetics of the chemical, the level of safety, the motive for experimentation on humans, precise safeguards for the human volunteers, and an overall proposal for future clinical trials. If everything is in order and the FDA approves the IND, then the phase I clinical trials may begin (Olejniczak, Gunzel, & Bass, 2001).
Phase I, II, and III Clinical Trials
The studies completed during phase I target the metabolism and pharmacologic actions of the drug in human volunteers. It also focuses on the possible side-effects that are correlated with the elevated drug doses, and the overall effectiveness of the chemical compound in humans. Phase I trials may include both healthy and/or diseased participants, usually 20 to 80 overall. During this phase, extremely low doses of the drug are given to a small number of healthy volunteers who are heavily supervised. Occasionally, diseased volunteers are used if the clinical trial revolves around a rigorous or critical illness. If these low doses show some signs of success, then the doses will be elevated gradually overtime. Approximately 70% of the phases I INDs are approved and passed on to phase II trials (ClinicalTrials.gov, 2009).
Phase II clinical trials take about 2 years to complete and use controlled tests to evaluate the overall effectiveness of the drug. It aims to prove the effectiveness by using roughly 100 to 300 patients who have the disease for which the drug is primarily used for. Phase II trials also verify the temporary side-effects and assess the overall risk in taking the drug. A limited number of patients are used during this phase due to the lack of evidence and data associated with the drug. Therefore, sufficient statistical analysis is performed on the minimum amount of volunteers needed to determine the effectiveness. The objectives of a phase II study include determining a dose that is valuable to the patient, the means in which the drug is administered, the assurance that the product is safe for human consumption, and also the appropriate dose level. The patient volunteers are monitored extremely closely and are evaluated incessantly. Approximately 33% of INDs submitted for phase II clinical trials are approved for continuation into phase III. The reason for this heavy drop in approval is due to the fact that the majority of drugs are proven to be unsuccessful. Other reasons for the high rate of rejection include having major safety issues and/or negative side-effects (George, 2003).
Phase III clinical trials can last several years and are the concluding step before the drug can be submitted for FDA approval. During this phase, researchers intend to validate the results from phase II with a much larger population across the country, usually around several hundred or even thousands of patients. Phase III trials are essential at demonstrating additional safety precautions, the best level of dosage, and the identification of the toxic, side, or adverse effects associated with the drug. These extensive, time-consuming trials can be extremely expensive, but are necessary to make sure that the drug is indeed safe for the patients. Approximately 27% of INDs submitted after phase III trials are approved by the FDA (Clinical Trials, 2009).
After the phase III trial has been approved, the new drug application, or NDA can be filed with the Center for Drug Evaluation and Research (CDER), a branch of the FDA. The information available in the NDA includes all of the results from the preclinical and clinical testing phases. It contains all documentation associated with the drug. This information includes the ingredients and manufacturing methods of the drug, the toxicity of the drug, how the drug behaves in the human body, the resulting data of all phases of clinical trials, and the future package insert or label. After the NDA is filed, the CDER can then process an independent assessment and make any additional recommendations that might be necessary for final approval. The time that it takes for to obtain CDER approval after the NDA is submitted has been greatly reduced over the past decade. This is due to the passing of the Prescription Drug User Fee Act of 1992, or PDUFA. This act intended to greatly reduce the time required for the review process by collecting monetary fees from the pharmaceutical industries to financially aide and speed up the review process. The CDER is now able to evaluate a standard drug application within 12 months of original submission. In the year 1999, the CDER approved 35 new drugs at an average of 12.6 months, which was close to the 12 month goal set in 1992. Standard applications usually involve drugs that are similar to older drugs that have already been approved. NDAs that have higher priority are drugs that are unique and will have a significant impact on a known disease. These higher priority applications are guaranteed to be reviewed within 6 months. The CDER has the right to ask for additional information at any time during the review process. Drug companies may also be asked to make necessary corrections to further enhance the drug for approval. Once the review process is analyzed in its entirety, the CDER passes the NDA to the FDA who has a final decision in which to approve or reject it (George, 2003).
If the new drug is approved by the FDA, the drug can then be marketed. However, if the drug application is rejected, the FDA will provide the applicant with the various reasons of why it was denied and what information and/or changes are necessary to further approve the new medication. Every now and then the FDA will grant a provisional approval on the drug. This provision may occur for numerous reasons such as a slight deficiency in the medication or perhaps an issue with the package insert. If all of the suggested changes are corrected in a timely manner, then the FDA will grant a final approval for the drug (Woodcock, 1996).
Phase IV Clinical Trials (Postregistration or Postmarketing Trials)
Some provisions are placed on an approved medication that might require the manufacturer to perform additional clinical testing, referred to as phase IV clinical trials. Phase IV trials, or postmarketing studies, examine the advantages and risks in a diverse population or a population with a higher risk associated with ingesting the new drug (Del Sorbo, Thompson, & Ranieri, 2009). Phase IV studies are significant because even well-designed phase III studies might not reveal every single mistake that could become evident once the drug product is approved for the market. It is at the discretion of the pharmaceutical company to perform postmarketing research on certain issues that may arise. These issues might revolve around the effects of long-term exposure to the drug, continual observation of the drug dosage, additional assessment of the drug interaction in young children, or to observe the effectiveness of the drug for any further supplementary safety measures. In phase III trials, the drug is only monitored in a specific number and group of patients that have the drug-targeted disease. Therefore, postmarketing trials expand their research to groups that were not studied in the previous phase, such as senior citizens or children. Postmarketing trials may also be extremely useful in determining an off-label or unlimited use of the drug. Medical doctors are encouraged to report all notable problems and possible complications with the new product. These complications can be reported using a reporting system called Medwatch, which document serious adverse events. These adverse events must be reported periodically by the pharmaceutical company for the first 3 years after it is approved by the FDA. The manufacturer is also responsible for reporting any severe and unanticipated adverse reactions (Junge, 2009).
Patent Protection and Trademarks
Patent protection is obtained from the United States Patent and Trademark Office, or USPTO. It can be filed while the preclinical trials are underway. Patent protection is important because it provides a safeguard for the person or group of people who have designed the new chemical compound that may become a profitable medication. Patents also protect individuals who have discovered a brand new use of an already accessible drug. Patents prevent other people from manufacturing, using, selling, or importing the patented drug. While the patent is still valid, it also prevents pharmaceutical companies from producing the drug in a generic form. After it has been issued to the new product, it is the individual's responsibility, not that of the USPTO, to strictly enforce the approved patent. Due to the extensive amount of time that it takes to develop a drug, it is imperative that the patent not be filed too soon or else the patent will expire before the drug is able to make a profit. If this were to happen, the individuals would not have enough time to recoup their excessive research and development costs (United States Patent and Trademark Office, 2009).
After the new pharmaceutical product has been approved for a patent, it is protected for a specific number of years based on a number of criteria: the category of drug, indication of disease, and use for the drug. Usually the patent is applicable for approximately 20 years from the date that the original application was filed. While the product is still under a patent, the pharmaceutical can be sold at an appropriate price that is determined by the drug company. With regard to the price, the drug company hopes to recoup the initial investment, reinvest the profit into new research and development, and provide some sort of monetary return to the initial stakeholders. In order for the pharmaceutical company to recover their investments, adequate patent protection is necessary. When the time comes for the patent to expire, this paves the way for the generic versions, and the earnings for the brand-name drugs are greatly reduced. Generic drugs put the strain on the pharmaceutical companies to maintain a line of newer, more advanced products. This supports the recurrent cycle of marketing the newer, more innovative pharmaceuticals, therefore replacing the drugs that are inadequate (Murphy & Topel, 2006).
A trademark can protect a word, name, symbol or design, or a combination of all four that may differentiate goods and services from those produced or sold by others and to provide an indication of the source of the goods. Towards the end of the phase III trials, trademarks can be submitted to the USPTO. Once the name of the chemical compound has been settled and the drug has been approved, the trademarks can be filed. Unlike patents, trademarks can continuously be renewed for as long as they are being used in the marketplace (United States Patent and Trademark Office, 2009).
The Cost of Drugs
Pharmaceutical companies play a major role in the global economy. New medications that are developed by these companies offer people an enhanced quality of care, better life expectancy, and better patient outcomes. All of these outcomes lead to an economic growth over time. It is apparent that the overall benefits and risks that the United States healthcare system are controversial. Benefits would include things such as new medicines and increased quality of care. Risks of the healthcare system include problems with healthcare coverage, the high costs of bringing a new medication to the market, and the possibility of newer drugs being ineffective. The healthcare system is and always will be under scrutiny and it is extremely imperative that they place a main focus on constantly improving therapeutic and scientific innovative techniques. New drugs are often viewed upon as an impending investment, not only for the patient themselves, but also for financial recovery and expansion (Murphy & Topel, 2006).
In 2006, economists from the University of Chicago reported that from the years 1970 to 2000, the overall life expectancy increased approximately $3.2 trillion per year to the national capital. It was ascertain that at least half of these earnings were a direct reflection of the progress made with one solitary illness, heart disease. Furthermore, estimations have been reported that even by making the smallest innovation against a major illness, such as heart disease, it would be extremely valuable to the economy in the future. By decreasing the cancer mortality rate by just 1%, the United States economy would see gains of approximately $500 billion. Furthermore, by discovering a cure for cancer it could be worth more than $50 trillion (Murphy & Topel, 2006).
The overall cost of pharmaceuticals is one of the debatable topics in improving the healthcare system. However, according to the Pharmaceutical Research and Manufacturers of America, or PhRMA, drug costs only represent about 10% of all healthcare costs and they actually decrease overall healthcare costs by keeping patients out of the hospital. An example of this decrease in healthcare costs would include the enhancement of specific drugs that lower blood pressure. This innovation would decrease the mortality rate by 89,000 and lower the hospitalization visits by 420,000 every year. These actions would save more than $15 billion each year in healthcare spending. This just goes to show that people should focus more on the insufficiencies in the healthcare system that comprise the other 90%, instead of the overall cost of prescribed pharmaceuticals (Platform for a Healthy America, 2009).