Today, development timescales are much longer, with a corresponding reduction in the potential sales window. This is leading to much riskier parallel processing, with development and testing work, such as drug delivery system design, running in parallel with the clinical development. Manufacturing process design may also now begin as soon as a candidate drug is approved for development; the manufacturing plant might be constructed during Phase 2 or 3 clinical trials and the product might be manufactured and distributed to pharmacies before the FDA or EMA has given final marketing approval.
This would enable doctors to write prescriptions for the new pharmaceutical the day after marketing approval was given. However, should marketing approval not be granted, all this investment will, of course, be wasted.
I have personal experience of a world-scale chemical plant for a pharmaceutical active ingredient being constructed, commissioned, mothballed and then demolished without ever making any saleable product when the candidate drug was refused its market authorisation. Why would companies take such risks? The aim is to reduce the time taken to bring a candidate drug to the patient; speed to market is one of the key metrics in this industry and weeks are important.
The increased risk involved in manufacturing also leads to major structural changes in the business model. The pharmaceutical industry developed as a set of fully integrated and self-sufficient businesses. In-house research scientists produced candidate drugs, which were then developed into saleable products; these were in turn manufactured, marketed and distributed.
However, the risks associated with blockbuster drugs have led to a considerable reshaping of the business, particularly in terms of manufacturing.
The telescoping of the development process leads to an increased risk of building manufacturing plant that you might never use. However, if your new drug is successfully launched and then turns out to be a blockbuster you may need to rapidly scale up your manufacture to meet the unexpected demand which may subsequently increase still further, requiring even more manufacturing capacity.
However, when the patent expires sales will nose dive and all this manufacturing capacity will be surplus to requirements. The initial response to this challenge was to attempt to design and build modular in-house multi-use manufacturing facilities that could be used to produce any active ingredient.
However, a more economical solution has been to outsource manufacturing to one or more toll-manufacturers, a practice which is now commonplace in the research companies. The innovating company will use a pilot plant to manufacture trial batches of active ingredient for clinical trials and to test out process design options. The bulk active ingredient used for product sales will, however, be manufactured by contractor s who is are much more able to match production with demand.
The use of toll-manufacturing increases flexibility, making it easier to scale production up or down to meet fluctuating demands. It also provides business resilience by enabling production to be divided between different locations and, finally, modern toll-manufacturers are often more knowledgeable about efficient process chemistry and have much lower operating costs, especially in India and China.
Outsourcing benefits in manufacturing have encouraged industry to extend it into most other areas of the business. For example, in AstraZeneca outsourced substantial amounts of safety assessment, development drug metabolism and pharmacokinetics to a contract research organisation. The pharmaceutical industry consists of a set of businesses in which shareholders can be persuaded to invest money with the expectation of receiving a return on their investment.
However, this industry is a high-risk business and thus the value proposition presented to potential investors is a little unusual, as is illustrated by the following case study: Company A has identified research that suggests that regulation of target B in human beings shows promise in producing a beneficial outcome for disease C.
Company A has also established that, at least in vitro, its candidate drug X has the potential to regulate target B. Investors should be aware that there is no certainty that drug X is actually able to regulate target B safely in vivo, or that any such regulation of the target will actually significantly influence the course of the disease concerned. As this example demonstrates, since the investment required is very large, long term and has a very high risk of failure, the potential return on investment must be very high if the necessary funds are to be forthcoming.
It is also worth repeating that, unlike many types of business investment where some saleable assets will be created by the investment, failure in this context is absolute; when a candidate drug fails, even in late stage development, there are zero assets available to offset the losses. Although this business model has many drawbacks, it has been sufficiently attractive to enough investors for a very successful industry to be developed over the last century, with a stream of new therapies appearing in the marketplace.
Alternative funding models continue to be proposed but to date none of these have been applied successfully. There are a number of people who believe that it is fundamentally unethical to make very large profits out of essential medicines and that either the state or non-profit organisations should undertake this task. However, the risk is simply too great for governments or non-profit companies to consider.
For example, imagine the response that you would get from a finance minister presented with the value proposition in the case study above for the development of a single drug!
This then has a direct impact on research priorities. It is clear that despite their size, pharmaceutical companies do not have sufficient resources to work in all areas of medical need; however, because of development timescales and the need to spread their investment risk, they must work on several candidate drugs simultaneously.
In choosing which areas to work in, a company must address the following question: assuming that our potential candidate drugs in this area can be successfully marketed, will they generate sufficient income during their patent life to cover their development costs, a portion of the development costs of previously unsuccessful candidates and, in addition, make an adequate return for the shareholders?
In other words, there needs to be a sufficiently large number of patients who require the drugs and also these patients must be able to pay for them, either directly or via insurance or taxation. It should, therefore, be no surprise that pharmaceutical companies heavily invest in research into chronic illnesses in the developed world, e.
As the time and cost of development increases and the useful patent life shrinks, the number of commercially unviable areas also increases. Pharmaceutical companies are frequently accused of not investing in some areas because they will make too little profit. A recent example was the public outrage that the pharmaceutical industry had not already invested in a vaccine active against Ebola.
However, the reality is that investing in areas such as this would inevitably lead to bankruptcy since in such areas the costs are certain to exceed the income, even if a successful product could be invented. In recent years another problem has emerged. However, we have now reached the stage where new drug development in this area has dwindled. One reason is the inherent difficulty of the research challenges; identifying compounds that will rapidly kill infectious cells in short timescales whilst being harmless to every other cell is somewhat difficult; however, the principal reason is economic.
Antibiotics are used by patients for very short periods and sales volumes are now insufficient to justify the necessary development costs. This is exacerbated by the fact that any new antibiotic would now be prescribed sparingly to ensure that antibiotic resistance was minimised. This problem was identified as early as 88 but only recently have serious attempts been made to find a funding solution. This is a major ethical dilemma for the pharmaceutical industry.
It has two parts, one less visible than the other. The less obvious issue is that it is a determinant of which diseases receive attention.
There may be a large number of potential patients, but if none of them could afford to buy a newly developed drug then such diseases are unlikely to be a research priority. The second issue concerns access to medicines that have already been developed. Both issues are now described as the access to medicines issue 90 and every major pharma company has a public policy relating to it, e. The first issue is being addressed by most of the major research pharmaceutical companies who are now involved, often with philanthropic partners, in altruistic drug-development programmes for diseases that predominantly affect the developing world.
For example, GSK has a major drug development programme on malaria, jointly with the Gates Foundation. Recently some pharmaceutical companies have begun to share their entire libraries of chemical compounds, allowing other researchers to look through them for promising drug candidates which the companies themselves are unable to take into commercial development.
It is primarily a problem with pharmaceuticals that are still in patent, since the price of the subsequent generic pharmaceuticals, which is available after patent expiry, is much reduced. Traditionally this issue related solely to the developing world and came to a climax in during the AIDS epidemic, where millions of sufferers from the disease in Africa were unable to afford the new retroviral pharmaceuticals that had been developed.
However, this exacerbates the problem of parallel imports. Differential prices for pharmaceuticals between developed and developing countries, especially where the price difference is substantial, provide opportunities for significant arbitrage: buying a product in the developing country at the low price, exporting it to the developed country and then selling it at an intermediate but highly profitable price.
During the AIDS crisis in Africa, GSK became so concerned at this possibility that they set up some clinics where the pharmaceuticals could be administered to the patient without the risk of the material being exported. This type of legal but unethical arbitrage has recently been happening so frequently within the European Union that artificial pharmaceutical shortages have ensued, leading to manufacturers trying to impose a quota system.
However, it is not only patients in developing countries that have difficulties arising from pharmaceutical pricing. In most countries pharmaceutical pricing is at least partially controlled by the state. Pressure on national health services and private health insurance companies is leading to increased downward pressure on prices and, in some cases, complete refusal to allow a new pharmaceutical to be prescribed.
The research pharmaceutical part of the industry is currently going through a major crisis as a number of issues come to the surface simultaneously. Thus, the industry as a whole would continue to deliver innovative pharmaceuticals which would be available to all at low prices after a short patent life.
The initial response to these problems by the industry was consolidation, with a number of large and sequential mergers and acquisitions followed by a number of very large ones. The 30 research pharmaceutical companies that existed in had by successively merged to become only 9 companies. This activity was very popular with the financial markets but, with hindsight, the benefits to shareholder value were difficult to realise.
In , J. The scale of the problem can be seen in Table 2. The second strategy has been to drastically reduce operating costs using a combination of direct cost savings from improved efficiency coupled with portfolio rationalisation, increased collaboration and extensive outsourcing.
As a result, the number of jobs in the global research pharmaceutical sector fell by ca. The most comprehensive data that currently exist come from the Swedish environmental classification system. Another recent study, carried out under the European Union Framework 6 research programme, has produced a similar outcome. Although the environmental risk can be shown to be very low, residues of many pharmaceuticals can still be detected in the aquatic environment using modern analytical techniques.
A number of environmental scientists continue to make the assumption that this means that all new pharmaceuticals should be biodegradable. However, this somewhat simplistic approach, even if it were possible to realise, would not be a panacea and is certainly not simple to accomplish given our current state of knowledge. There are a number of pharmaceuticals that are biodegradable, but this has happened by chance and none of our current pharmaceuticals has been designed with this in mind.
In other words they have to be stable enough to remain unchanged during a realistic shelf-life and to be able to be transported, unchanged, though various pathways in the body to reach the site where their effect will be exerted. Since most pharmaceuticals are taken orally, this means being able to transit through the highly acidic stomach. Not only is stability needed for the treatment to be effective, but instability can result in side effects caused by the toxicity of breakdown products, particularly in the liver.
The ideal pharmaceutical would therefore be a substance which only began to break down after it had been excreted by the patient. However, producing pharmaceuticals that are more degradable in the environment will not necessarily eliminate environmental residues.
The very low environmental residues that are currently being detected represent the equilibrium concentration reached between a constant input from wastewater treatment plants and the degradation rate in the environment. The data from the Swedish environmental classification scheme demonstrate that although very few existing pharmaceuticals are rapidly degraded in the environment, relatively few of them are highly persistent either, and most pharmaceuticals appear to degrade, albeit slowly.
However, our objective, taking this precautionary approach, is not to produce degradable pharmaceuticals but to reduce residue levels in the environment as far as possible without compromising the health of patients. Increased degradability of pharmaceuticals is one way that this might be achieved but there are many other ways to achieve the same endpoint. One of the drivers of research in the pharmaceutical industry is to improve the effectiveness of human pharmaceuticals.
Consequently, research teams are always trying to make drugs work better in the patient and most of the improvements being continuously targeted in drug discovery and development teams will also produce a lower environmental footprint. Table 3 shows several of the pharmacological objectives that would deliver improved patient benefit, alongside the environmental improvements that would ensue if that objective were reached.
The first three of the criteria listed in the table would lead to lower residues of active substances entering the environment; in other words, reduction at source. The last two would lead to even lower potential impact of the residual active material on ecosystems. Current developments are already leading to candidate drugs with a lower potential for environmental impact.
For example, a better understanding of drug metabolism and pharmacokinetics can result in lower doses being administered to achieve the same therapeutic effect. Similarly, shorter duration of therapy, better targeting and improved drug delivery combined with increased specificity all lead directly to smaller emissions from the patient to the environment and thus lower environmental residues.
However, two technical revolutions are underway which may improve this situation and may also reduce the overall environmental impact of the industry. The first of these is the advance of biopharmaceuticals. However, advances in our understanding of genomics and proteomics, coupled with our increasing technological capability to manufacture very large molecules, are leading to a rapidly growing interest in the use of biological as opposed to chemical-based therapies.
The first biopharmaceutical, synthetic insulin, developed by Genentech and marketed by Eli Lilly, was approved for sale in and by there were biological pharmaceuticals that had been approved by the US FDA with a further under development in the USA alone.
The fastest growth is in the area of monoclonal antibodies, which are components of the human immune system and are considered by some to be the perfect human medicines. They have major therapeutic advantages. Their high potency means that patient doses can be small, which subsequently then requires only small-scale manufacture. They have exquisite specificity and can be targeted to human receptor sub-types responsible for pathology or disease; thus they have substantially less potential for side effects.
These proteins are then rapidly metabolised by the human body to produce fragments with no mammalian biological activity, thus avoiding the possibility of producing metabolites with undesirable pharmacological activity. From an environmental perspective these substances appear to offer major advantages; most of these compounds produce little if any residues of the active substance, which is in any case much less likely to exert any adverse impact on the ecosystem, since it is specifically designed to interact only with a diseased human receptor.
However, the full environmental relevance of these substances is not yet clear. Biopharmaceuticals are not all easily biodegraded, and modified natural compounds even less so. Structurally related compounds such as plasmids have already been detected in the environment and it is known that the protein structures known as prions are very environmentally stable.
The second therapeutic revolution also stems from our improved understanding of genomics, although it is still in its infancy. It was suspected that this was due to the slightly different genetic make-up of individual patients, but lack of appropriate experimental techniques meant that this could not be further investigated. However, the recent rapid advances in the mapping of the human genome and subsequent development of the scientific disciplines of genomics, proteomics and metabolomics is leading us to a better understanding of the molecular signals of many diseases.
The expectation is that molecular screens combined with clinical data will point to more precise treatment options for each patient sub-group. This should enable much more precise and effective prescribing to occur which will, in turn, mean less overall drug use, since every prescribed dose will be effective first time. The research pharmaceutical industry remains beset with problems, for most of which there do not appear to be obvious solutions. Although it has exclusive rights to the sale of a new drug during its patent life: increasing regulation is leading to additional costs and longer development times with consequently reduced times to patent expiry; increasing risk aversion by executive management teams is contributing to a slowdown in the appearance of novel pharmaceuticals; reducing risk tolerance in patient populations and regulatory bodies is leading to a lower success rate for marketing authorisation approvals; cost pressures within national health services are leading to progressive downward pressure on prices; market penetration by generics is increasing rapidly; and many people consider that the current research pharmaceutical business model is no longer sustainable, but no-one has yet come up with a better one.
However, because of the increasing domination of drug-development pipelines by biopharmaceuticals, we can be certain that the next generation of human pharmaceuticals will leave significantly smaller residues in the environment than those that result from the use of current medicines. No non-target effects. Leung Toxicol. Clarke J. South Aust. Hamarneh Med. Jones Pharm. Kochweser and P. Schechter , Life Sci. Greenwood and A. Murrell Lancet , , 1 , 80 CrossRef.
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Larsson , C. Paxeus , J. Yang , J. Ren , Y. Zhang and K. Li , Environ. Thomas and K. Kummerer and M. Larsson Philos. Nielsen , P. Lanzky , F. Ingerslev , H. Pharmaceuticals in the Environment , K. Cunningham , M. Buzby , T. Hutchinson , F Mastrocco , N. Parke and N. Roden , Environ. Cuthbert , M. Taggart , V. Prakash , M. Saini , D. Swarup , S. Upreti , R. Mateo , S. Chakraborty , P. Deori and R. Jobling and R. Meanwhile, synthetic organic chemistry evolved as an industrial discipline, especially in the area of creating dyestuffs derived from coal tar.
It was only a short step from staining cells to make them more visible under microscopes to dyeing cells to kill them. Chemists soon modified the raw dyestuffs and their by-products to make them more effective as medicines. Early products of research continue to have application today; for example, N -acetyl- p -aminophenol, the active ingredient in Tylenol and Panadol, is a fast-acting metabolite of the analgesics acetanilide and phenacetin created in German laboratories in the s.
In , a chemist at Bayer, Felix Hoffmann, first synthesized aspirin, another staple of our medicine cabinets. The end of the 19th century also saw the development of several important vaccines, including those for tetanus and diphtheria. A theory relating chemical structure to pharmaceutical activity emerged from the interplay of experimental results from animal and human tests using vaccines, antitoxins, and antibodies with chemical knowledge about dyes and their molecular structures.
This structure-activity theory inspired Ehrlich to pursue a long and systematic course of research that resulted in the antisyphilitic Salvarsan, often considered the first systematically invented therapy. The progressively more important role of the chemist and chemical science in pharmaceuticals in the earlyth century is mirrored in the history of the American Chemical Society's Division of Medicinal Chemistry.
It was founded in as the Division of Pharmaceutical Chemistry one year after ACS instituted a divisional structure. Chemists in the U. But U. Those activities were largely monopolized by German chemists working in conjunction with the major German chemical companies. Supply, as Lilly saw it, was now properly positioned to keep pace with growing demand.
Despite the distance companies like Lilly and Pfizer had traveled from the world of snake oil, they were still largely on the sidelines when it came to basic scientific research during the first three decades of the 20th century.
Sickle cell anemia had just been described as a disease. Rockefeller, and the first X-ray machine was put into use. Offsetting these medical advances, World War I killed The Spanish flu followed, killing in and nearly 5 percent of the entire human population. Cholera, malaria, the plague, polio, smallpox, diphtheria, syphilis, gonorrhea, hookworm, and typhus plagued millions more. And while infectious diseases and traumatic injuries took the greatest human toll, and consumed the majority of public resources, by , changing survival rates caused entrepreneurs like Eli Junior to start focusing on the chronic diseases that afflicted those well along in years.
Life expectancy for newborns in the US, with improvements in water, food, transportation, and housing, had risen from 47 years to 57 years in the two decades between and Eli Junior envisioned acute diseases giving way to those that would require long-term management and, most important, long-term intake of prescription medicines.
Drugs cure people. He was also keen on starting a medical research arm inside the company, and the man he found to drive the effort was George H. Alec Clowes, a bench scientist who had spent the previous 18 years at Roswell Park Memorial Institute, a cancer laboratory and hospital in Buffalo, New York.
Eli Junior hired him and gave him free reign to find the next big discovery in medicine. Almost immediately, on December 28th, , Clowes sought out J. The diabetes researchers from the University of Toronto had been working with an extract secreted by the islets of Langerhans, groupings of specialized insulin excreting cells within the pancreas. By injecting this extract, called isletin, into a lab animal whose pancreas had been removed, they had managed to lower soaring blood sugar levels by 40 percent.
Clowes made the case that what the scientists needed were the resources of a commercial firm, and that Lilly would be more than happy to partner with this academic lab, bankrolling the research with full support not just for purification and large-scale production, but for dosage setting and marketing as well.
The scientists rejected Clowes outright. Hoping to provide their discovery at low cost to those needing it, the scientists had already sold the patent to the University of Toronto for one dollar. For almost a year, the university tried to scale up production on its own and failed miserably. Faced with unprecedented demand and little if any supply, the university called Clowes, who had been waiting patiently in Indianapolis.
The university worked out a deal with Lilly to become sole distributor for one year, royalty-free, in exchange for a 28 percent of each batch.
Again, the hope was that if drug companies acquired the rights at little or no expense, they would keep their prices low and even the poorest would benefit. Accordingly, in those early days of insulin therapy, price was not a major concern, but the larger issue arose almost immediately and haunts the Medical Industrial Complex to this day—the question of fair and equal access to life-saving medicines.
In April , a young girl named Elizabeth Hughes was diagnosed with diabetes. She was not just any Hughes—she was the daughter of Charles Evans Hughes, two-time governor of New York and an associate justice on the US Supreme Court, who had resigned from the bench to become Republican Party candidate for president in
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