1 UNDERSTANDING the PHARMACEUTICAL INDUSTRY
1.1 Development of the industry
1.1.1 Origins
1.1.2 Aspirin
1.1.3 Antibiotics
1.1.4 Rational Drug Design
1.1.5 The Introduction of Regulation
1.1.6 Regulatory Regimes
1.2 Business Processes
1.2.1 Drug Discovery
1.2.2 Drug Development
1.2.3 Manufacturing
1.3 Commercial Pressures on the Industry
1.3.1 The Blockbuster Model
1.3.2 The Generics Industry
1.3.3 Intellectual Property
1.3.4 Litigation and Liabilities
1.3.5 Commercial Responses
1.4 Novel Therapies
1.4.1 Genetic Technologies and Personalised Medicines
1.4.2 Gene therapy
1.4.3 Epigenetics
1.4.4 Monoclonal Antibodies
1.5 Related industries
1.5.1 Biotechnology and Biopharmaceuticals
1.5.2 Vaccines
1.5.3 Medical devices
1.5.4 Other Related Industries
Annex Some Major Companies in the Pharmaceutical Industry
1.1 Development of the Industry
An awareness of how pharmaceuticals and the pharmaceutical industry have evolved makes it easier to understand the modern industry: its manufacturing methods, the strict regulatory environment, the health issues affecting workers, and the social and ethical issues faced today. Professional hygienists need such knowledge in order to be credible with their technical and managerial colleagues in industry. It is not necessary for students to remember all the details of the historical events mentioned below, or to know about all the individual pharmaceuticals discussed, but knowledge of the specific pharmaceuticals that your company works with will prove very useful. Key learning points are summarised at the end of each section.
1.1.1 Origins
The pharmaceutical industry is concerned with the manufacture of drugs. A drug can be defined as “any chemical substance, synthetic or natural, of known or unknown composition, which is used as a medication to prevent or cure a disease.” There are many types of drugs. They can be categorised into around 15 classes by site of primary action (gastro-intestinal system, cardiovascular system, respiratory system etc.) then subdivided into around 100 further subgroups by drug type - antacids, laxatives, anticoagulants, analgesics, cytotoxics to name but a few.
Up until the industrial revolution the pharmaceutical industry only existed in the form of apothecaries and pharmacies that offered traditional remedies. It was not until the 1800s that an industry involving large scale manufacture started to emerge.
1827 – Heinrich Emanuel Merck worked in the family pharmacy in Darmstadt, Germany and started to isolate all the known alkaloids and sold them to other
Chemists and physicians.
1842 – Thomas Beecham started selling “Beecham’s Pills”, a laxative tablet, building up a network of sales throughout the north of England and by 1859 opening the world’s first pharmaceutical factory.
1849 – In the USA Pfizer is founded, initially making Sanonin, an antiparasitic. During the American Civil War they expanded to meet the demand for painkillers, preservatives and disinfectants.
1858 - Edward Robinson Squibb, set up a laboratory supplying the union armies in the civil war. Despite being badly burned by an ether explosion and the laboratory being burned a further two times, by 1883 the company was manufacturing 324 products and selling them around the world.
1876 - Col Eli Lilly a pharmacist and veteran of the American Civil War began his medical wholesale company. Lily pioneered new methods in the industry, being one of the first to focus on R&D as well as manufacturing.
1888 - As a result of the demand for more exact dosing and sophistication of drug formulation, the physician and pharmacist Dr. Wallace C. Abbott, using the active part of a medicinal plant, known as the "alkaloid," formed tiny pills called "dosimetric granules," which provided more accurate and effective dosing for his patients than other treatments available at the time. From these modest origins inside a physician’s residence, was born Abbott which is now AbbVie, Inc.
During the later half of the 19th Century Switzerland also developed a pharmaceutical manufacturing industry. Companies set up to manufacture dyestuffs realized that their products had anticeptic qualitieis and started to market them as pharmaceuticals. A lack of patenet laws in the country companies to manufacture and sell products made by other companies. Novartis, Roche and the Basel hub of the pharmaceutical industry all have their roots in this boom.
Key learning points:
· The first pharmaceutical companies grow out of traditional pharmacies.
· Early pharmaceuticals were based on natural remedies.
· There was no clear dividing line between prescription medicines and other products.
· Modern pharmaceutical manufacturing has its origins in the fine chemicals industry of the 19th century.
· Even today, the geographic distribution of the major companies reflects this history.
1.1.2 Aspirin
Aspirin was perhaps the first synthetic pharmaceutical and remains the most widely taken drug in the world. The story of its development and subsequent use illustrates several principles that have come to typify the pharmaceutical industry.
Ancient Sumerian and Egyptian texts recommended willow bark for various complaints. Greek, Roman and Islamic medical authors noted its power to reduce pain and relieve fevers. However, its tendency to cause inflammation and occasionally bleeding of the stomach lining considerably diminished its utility.
In 1828 the German chemist Joseph Buchner isolated the active ingredient, a yellowish, bitter tasting substance that he called salicin (salix being the Latin for willow). Two years later Johann Pagenstecher, a Swiss apothecary, extracted the same material from the meadowsweet plant, whose botanical name spirea later suggested the brand name aspirin.
In 1838 Raffaele Pirea succeeded in converting salicin to salicylic acid. This compound proved to be a more useful remedy, but unfortunately it irritated the stomachs of some patients. In 1853, the French chemist Charles Gerhardt prepared its acetyl ester, which had similar analgesic, anti-inflammatory and fever-reducing properties to salicylic acid but was less harmful to the stomach. The ester was not hydrolysed until it reached the alkaline environment of the small intestine.
Bayer, a dyestuffs company established in 1863, developed a new industrial synthesis for acetyl salicylic acid and commercialised it as aspirin in 1899. Early synthetic drugs were tested haphazardly and often failed to fulfil all the marketing claims made but Bayer took a more systematic approach. Both commercial and medical factors contributed to the drug’s success. Aggressive advertising hammered aspirin’s reassuringly non-technical name into the public consciousness, while astute lawyers defended its trademark status in every important marketplace. Taking a tablet to relieve distress quickly became an integral part of western culture.
The national rivalries and conflicts that characterised this period also had their impact on the developing industry. Bayer had the aspirin trademark and its US assets seized during World War One, whilst “American” Merck (now Merck & Co. in the US or Merck Sharp & Dohme [MSD] elsewhere) was compulsorily split off from its Germany parent company (Merck KGaA) at the same time. Bayer also had its Russian subsidiary seized during the Russian revolution. This disruption to Germany’s position as the leader in pharmaceuticals in the early 20th century by the war meant that others, particularly in the US, could take relative advantage. The beginnings of the globalisation of the industry were seen both before and after the war – in the UK, import duties incentivised many foreign companies such as Wyeth, Sandoz, CIBA, Eli Lilly and MSD to set up subsidiaries in Britain in the post-war years.
In the 1950s and 60s the dominant position of aspirin was challenged by paracetamol (acetaminophen) and ibuprofen. The use of aspirin by children was discouraged in the 1980s because of a suspected link with Reye’s syndrome, a very rare but extremely unpleasant childhood illness. Yet as its mechanism of action has been researched, new uses of aspirin have emerged. It has been shown to reduce the formation of blood clots, by blocking the production of thromboxane, a lipid which encourages the clotting of blood through its action on platelets. This can reduce the likelihood of cardiac failure or strokes. Recent research also indicates that aspirin may be effective against some varieties of cancer.
Key learning points:
· Synthetic molecules often have fewer side effects than the natural products.
· Systematic testing of efficacy is essential with a new pharmaceutical.
· Marketing is key to the commercial success of new drugs and the industry has often been accused of being too aggressive.
· Defence of intellectual property rights through patents is a major concern for companies that discover and develop new drugs.
· Concern about unforeseen side effects sometimes arise when the drug reaches a mass market.
· New indications for the drug to treat other health conditions sometimes emerge later.
1.1.3 Antibiotics
The use of toxic metal compounds to treat syphilis infection, caused by the bacterium Treponema pallidum had been known since the days of Paracelsus in the 16th century though many people would have died from the toxic side effects. Paul Ehrlich announced the first true antisyphilitic, later patented as Salvarsan in 1910 after testing many hundreds of compounds. It became the mainstay of treatment until the discovery of penicillin and led to the use of the term “magic bullet” for pharmaceuticals that selectively targeted a disease-causing organism.
In the early 20th century common bacterial infections were often fatal. The discovery of antibiotics, which kill bacteria, transformed survival rates and life expectancy.
Penicillin antibiotics stem from a chance discovery by Alexander Fleming in 1928. He observed that certain Penicillium moulds killed bacteria and isolated from them an extract which proved to have impressive potency. The active ingredient was named penicillin. Chain and Florey in Oxford, UK developed the first production method involving fermentation to culture the mould and extraction. Large scale production of penicillin began in 1940. Natural penicillins degrade easily in acid, so have to be injected into the blood stream and cannot be taken by mouth.
Figure: Alexander Fleming (source: Calibuon via English Wikibooks)
Elucidation of the beta-lactam chemical structure of penicillin led in the 1960s to the incorporation of a number of different side chains (shown as R in the diagram), giving a range of semi-synthetic antibiotics. The first major development was ampicillin, which offered a broader spectrum of activity than the original penicillin. Later, amoxycillin proved highly effective against Gram-positive bacteria such as staphylococci and streptococci though infections caused by Gram-negative bacteria such as salmonella and pseudomonas do not respond. Penicillins can also provoke severe allergic reactions in some patients so they are not suitable for everyone.
Amoxycillin remains a broad spectrum antibiotic of choice but penicillins are now subject to increasing antibiotic resistance. Bacteria have adapted to produce enzymes called beta-lactamases which breakdown the beta-lactam structure of the antibiotics, rendering some essentially useless. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged.
Industry efforts to find substances that would destroy the beta-lactamases were unsuccessful until in 1975, clavulanic acid was isolated from a soil microorganism and found to be an effective inhibitor of beta-lactamases. When used in combination with amoxicillin, as co-amoxyclav (trade name Augmentin), this proved to be highly effective and it remains one of the world’s bestselling pharmaceuticals.
Much of the problem of penicillin resistant bacteria results from the overuse of antibiotics. Penicillins have often been prescribed for common colds and flu, which are viral infections and do not respond to antibiotics. They have even been added to cattle and poultry feed to promote growth and improve yields. This overuse has resulted in pathogenic bacteria having abundant opportunity to come in contact with the drug and mutate into resistant forms. In most cases, the drug resistance genes of bacteria are carried on plasmids (small DNA molecules that are physically separate from, and can replicate independently of, chromosomal DNA within a cell). Plasmids can be passed from cell to cell, allowing for a drug resistance to be passed to a large group of bacteria and to different types of bacteria. Some plasmids have as many as 8 drug resistances on them. For decades, the pharmaceutical industry has been searching for alternative antibiotics.
In 1948, Giuseppe Brozu from Sardinia published a report of another group of antibiotics cultured from a strain of mould that grows on sewage, the cephalosporins. Years of research finally showed that these compounds also had a beta-lactam structure (see Figure). Again, the commercial exploitation of this class of drugs depended on the development of a semi-synthetic route involving removal of the side-chain to give 7-aminocephalosporanic acid and then substitution of an artificial side-chain. The cephalosporins proved to have activity against both Gram-positive and Gram-negative bacteria, and their effectiveness has been enhanced in successive generations of drugs. And again, they have proved susceptible to the development of antibiotic resistance, though it has been less of a problem because the cephalosporins have not been as widely used as the penicillins.
Another major antibiotic, streptomycin, was discovered in 1943 and found to be effective against tuberculosis (TB), one of the world’s major killer diseases. About one-third of the world’s population carries the bacillus but people typically do not develop the disease unless their immune system becomes impaired. In countries where poverty and overcrowding are the norm, it causes around 1.5 million deaths each year. At one time it appeared possible to eradicate the disease, but by the mid 1980s it became clear that resistant forms of TB had developed and infection rates were no longer falling. This was found to be because people with the disease failed to complete their lengthy course of treatment once the symptoms subsided, and the bacteria remaining in their bodies, which had had prolonged exposure to the streptomycin were able to adapt. Infection rates began to rise, compounded by the spread of AIDS which compromises the immune system, and the availability of global air travel. In 1993 the World Health Organisation declared a global emergency for TB. More modern drugs have continued to show some effectiveness but “totally drug-resistant TB” was first observed in 2003 and was becoming widespread by 2012.
Further important antibiotics in the same class as streptomycin include neomycin (1949), erythromycin (1952), vancomycin (1956) and gentamycin (1963). Vancomycin has been called the “antibiotic of last resort“ because until recently no bacteria had developed resistance to it. Vancomycin resistant Staphylococcus aureus (VRSA) has now been identified. Use of vancomycin is heavily restricted to prevent resistance spreading further.
Antibiotic resistance now poses a major threat to human health, with the clear possibility of a return to the situation of the early 1900s where simple infections can be fatal. Research has offered a number of leads to the development of new classes of antibiotic that act in different ways and might overcome the problem of resistance for a while. However, antibiotics have become so cheap that developing new ones offers little prospect of recouping the development costs and many commercial companies have cut their research programmes.