Origins of the Pharmaceutical Industry
Origins from Pharmacy:
- Natural substances have been used for healing for 1000s if not 100,00s of years.
- 18th, 19th C - Began the chemical analysis of traditional medicinal plants e.g Foxglove (Digoxin - heart failure) Opium Poppy (Morphine - Pain)
- 19th C - Active ingredients become frequently prescribed - need for large quantities of good quality extracts resulted in medical collaboration with chemical industry. A few pharmacies became industrialised.
Origins from Chemistry:
- 19th C - major chemical advances, huge productivity, isolation of many active compounds from plants. First synthetic dyes "Analline dyes" made from coal tar. Dyes could be used to synthesize many useful substances.
- Many chemical dye manufacturers branched into pharmaceutics. Especially in Germany. Bayer synthesised "Aspirin" (1897) and marketed it worlwide in 1899.
- In Europe the requirement for large scale quality controlled production of drugs was the driving force for the development of a pharmaceutical industry.
Origins of the Pharmaceutical Industry
Origins from Microbiology
- 19th C - microorganisms cause disease. Dyes as drugs "Chemotherapy" In 1899 Methylene blue used to treat patients with malaria continued to 1945 (but turns eyes blue and urine green)
- 1909 - Ehrlich developed arphenamine, arsenic compound the first effetive drug for syphillis (superseeded by safer neo-salvarsan until 1950, replaced by penicillin)
- Futher development of organic arsenic compounds and development of dyes 0 ked ti the sulphonamide antibacterials (bayer - sulphonamide of chrysoidin)
The Antibiotic Era
- Prior to 1920s - drugs used to relieve symptoms, diseases poorly understoof
- 1920s and 1930s - major discoveries in chemotherapy (sulphonamides and penicillin - 1928 Fleming)
- 1940 - florey and chain purified penicillin and demonstrated its effectiveness as an antibacterial.
- Early 1940s are condiered the beginning of the modern pharmaceutical industry - chemical synthesis, together with microbiology led to the development of drugs at an unprecedented rate,
Emergence of the Pharmaceutical Industry.
Pharmaceutical industry today is a product of post-war growth.
1940s-1960s regarded as the "Golden Age" - wide range of diseases came under control. "miracle cures" spectacular benefits to patients.
1970s-1980s huge commitment to research and development, intensive marketing and promotion but only a few successes not as much as the Golden Age.
The Modern Pharmaceutical Industry:
- Many pharmaceutical companies continue to be strong
- Sales of the top major companies over $4oo billion in 2010. Around $70 billion reinvested in research and development, cost to bring a new drug to market is enormous so companies may share the costs of R+D through joint ventures.
- Mergers and takeovers hav created huge conglomerates e.g (Glaxo + Wellcome) + (SmithKline French + Beechams) > GlaxoSmithKline
The Pharmaceutical Industry
The Pharmaceutical Industry discovers, develops and manufactures drugs and medicines. Each of these processess is highly government regulated. This is to ensure the safety, quality and efficacy of all medicines and drugs.
The Modern Pharmaceutical Industry:
- Companies are Global and Multinational (worldwide sales)
- Spends billions on research and development.
- The industry provides drugs and medicines
- Doctors decide which drugs/medicines to use (POM)
- Pharmacists dispense POM (more potent drugs) and advise on OTC medicines
- Patient is the "customer"
- Government/insurance pays the bill
Pharmaceutical Industry Problems
- Tighter govenment regulatory controls on devlopment and marketing - requirement for safety ( orginated in the thalidomide scandal 1960s) requirement for efficacy.
- Governments want to reduce costs of helath care (cheaper generics now favoured, created after patent runs out, reduces profits for industry)
- Success of companies depends on their innovation - other companies may develop similar drugs which dilutes any new market
- Research and development commitment is out of balance with cash flow - it costs $100s of millions to bring any new drugs to market - companies must therefore develop "blockbuster" drugs
- Prolonged development time for a new product means a reduced time (for sales and profits) when drug is under patent (patent llife is only 20 years)
- Earlier "Random Synthesis" approach to finding drugs is now too hit and miss. Companies must be more sophisticated and must adopt a rational drug design.
Criticisms of the Pharmaceutical Industry
Business Ethics - excessive marketing, too much drug promotion, cutting scientific corners, inflated prices, unjustified profits.
Unethical behaviour - Very damaging to the repuation of the industry. Voluntary code of practice - adopted in 1981
Conflict between PROFIT and HEALTH BENEFACTOR in a successful pharmaceutical company
Success in finding drugs for conditions where there is still a strong need - helps to restore tarnished status
New drugs and medicines
Bringing a new medicine onto the market is a gamble.
From discovery of a new active compound to the launch of a new medicine requries 10-15 years.
And an estimated investment of $1 to $2 billion, breakdown of costs
- 10% - tax, profit
- 15% - research and development
- 55% - basic costs, raw materials, labour advertising
The discovery and development processs
- Requires finance, long-term commitment, multi-disiplinary staff and coordinated interaction of scientists and professionals from many disciplines.
The identification of potential new drugs and the identification of a "lead compound" to take into a development phase (Called a "Drug Candidate in the UK). Drug discovery is expensive, unpredictable and time - consuming. "Lead (leading) Compound" - has pharmacologicalor biological activity likely to be therapeutically useful but may require modification to fit better the target.
Major sources of new drugs
- Chemical synthesis (chemical modifications of old "lead compounds" are screened unsing high-vol, rapid, in-vitro receptor binding assays) - costly and low in efficiency - but many new drugs discovered
- Old compouds with a new uses - new drug effects discovered purely by chance
- Natural Products (from plants, marine organisms, bacteria, fungi, animals) 60% current drugs originate from plan/microbial sources, only a fraction of earths living species have been tested.
- Targeted drug design and synthesis - based on current knowledge of cellular/biochemical mechanisms and receptos , computer/theroetical models, then chemical modifications are made.
Resources used to identify new drugs - Chemical libaries, computer designing, new biological targets/medical conditions, advances in biological knowledge, human genome project, biological agents as drugs, automated screening methods
Identification of a "lead compound" to take into the development phase
- Multiple screenings must show drug activity in the therapeutic areas we are looking for
- Once potential drug activity is identified, further screens are then performed eg whole cell assays to evaluate the ability of the new candiate drugs to reach the site of action
- Optimization of molecular structure to produce a new drug candidate to take into the development phase as a "lead compound"
Key issues in Drug Discovery. Efficacy and speed because of:
- High failure rate - over 80% of new drug candidates fail to make it to market
- Other companies - may be working on competitor new drugs
- Patent protection - only lasts 20 years from the discovery of the drug. After this time, other compaies can make and market "generic" medicines containing the same drug
This phase encompases all the activities needed to turn a "drug candidate" into a medicine that is safe, effective and high quality.
1. Chemical process development - Design of a chemical process that allows manufacture of bulk quantities of high quality of drug. Optimization of synthetic route and chemical process that is cost effective, enviromentally friendly, scalable to large quantities. A high spec process is required by regulatory authorities because; low levels of impurities (>99%), sensitive and validated analytical methods, GMP (good manufacturing practice)
2. ADME - investigations to understand how the new drug is handled by the body. This is undertaken in animal and human studies. Absorption (how rapidly and to what extent), Distribution (of compounds, time of residence), Metabolism ( what metabolites formed), Excretion (route, rate, half-life).
3. Toxicology - Cell culture, bacterial and animal testing (determine if a new drug has toxicity problems, to estimate a dose which activates maximum effect with minimum toxicity). In-vitro tests (bacterial mutagenesis tests). Animal testing (Acute toxicity - single doses weeks, Chronic toxicity - 6-12 months, Carcinogenicity and Reproductive toxicity - 18-24 months). There is a huge effort to replace lab animals with cells or tissues.
4. Pharmaceutics - Preformulation (tests to understand properties, solubility, chemical and physical stability, excipient compatibility. Formulation (The design and optimisation of new medicines. Formulations for early clinical trials are kept simple, solutions and capsules). Stability testing (storage of medicine and pack at different temperaturers and humidities, how rapidly does it degrade > shelf life)
Clinical Trials - Phase I + II
Phase I - Clinical Pharmacology and Toxicology trials
- To determine ADME, pharmacokinetics, bioavailability
- Dose related side effects
- 50-200 healthy volunteers (don't have the disease, not children, reproductive women, elderly) given single doses/ rising doses. To determine smallest efffective and highest tolerated dose.
- 70% of potential new drugs pass phase I.
Phase II - Clinical investigation of therapeutic effect
- About 1-2 years
- Aim to establishment, suitable dose, dose frequency, efficacy of the drug in the human disease, duration of effect, common side effects/ risks
- 100-400 patients WITH the disease are given different doses/ frequencies, the study design may be "blind", "cross over", "double-blind" to avoid bias
- 33% of new drugs pass phase II.
Clinical Trials - Phase III + Phase IV
Phase III - Large scale therapeutic evaulation in patients
- Many studies over 3 or more years, thousands of patients in many hospitals. Randomised, double blind, placebo- controlled trials to avoid patient and physician bias.
- To demonstrate better efficacy or benefit to risk than placebo and competitors product, short and long term safety, drug related adverse effects, drug interactions.
- If results show a statistically significant improvement on current treatment, then the company will proceed to submitting a drug/medicine dossier to MHRA or FDA for marketing approval
- 25% make it through phase III.
Phase IV - Post marketing survellience or pharmacovigilance (happens after regulatory approval)
- Monitoring of the new medicine in use, thousands/millions of patients, accumulation of data on long-term efficacy, toxicity, side effects. Medicine/drug can be withdrawn if significant adverse effects emerge - yellow card reports.
- How does drug compare with others? Any evidence that drug is useful in other medical conditions?
A "dossier" of all the evidence is submitted to the "regulatory body" of all countries you wish to market a pharmaceutical product in.
Regulatory bodies - MHRA (UK) EMA (Europe) FDA (USA) DCA (Malaysia) SDA (China) - These are government agencies that regulate and approve medicines. Sucessful "regulatory approval" allows registration/ licensing in that country allowing use, sale or prescribing of that drug/medicine.
In the UK, regulatory approval by the MHRA > granting of a Marketing Authorisation MA (Product Licence)
Examples of evidence in the dossier - all development work undertaken, all plans to ensure quality, efficiacy and safety, all clinical tests and data, manufacture, packaging, labels, leaflets, post marketing surveillance, huge document. There is a lengthy period of assessment and questions are asked.
Medicines are controlled very tightly worldwide - lucrative, huge potential for fraud, false claims of effectiveness etc, counterfeits are common
Marketing and Patenting
- Promotion of the new product is essential for a return on the development costs and a profit.
- Aims - to establish awareness of a new drug, to maximise your market share
- Strategy - is planned in advance of regulatory acceptance, size of the existing and potential market, clincial profile of the drug, competitor drugs
- Protects your exclusive right to manufacture.
- Only lasts 20 years from discovery, and 12 years can be taken up in development
- The following can be patented: The drug, the chemical process, the method of use
Research and Development
In summary - research and development:
- R+D in the pharmaceutical industry in lengthy, risky, expensive and long term
- Primary goal is to maximise profits
- Huge strategic investment decisions have to be made by company directors (which therapeutic areas? which new drugs to take as candidates to clinical testing?, R+D organisation)
All pharmaceutical products must have proven, SAFETY, QUALITY, EFFICACY
Governing law in the UK:
- EC 1965 first major pharmaceutical legislation
- UK - Medicines Act 1968
- UK - The Human Medicines Regulations 2012 - incorporates all previous legislation
Authority to License is with the Minister of Health - various advisary bodies eg commiission on human medicines
Regulatory body is the MHRA which grants the MA
After MA is granted the medicine is examined by NICE to decide if it can be prescribed/used by the NHS
Medicines and Healthcare products Regulatory Agency (MHRA)
- The UK "regulatory body" the government agency responsible for licensing new medicines for use.
- It ensures the safety quality and efficacy of medicines and medicinal devices to the public
- All new medicines must be approved by the MHRA and issued with a marketing authorisation (MA) before they can be prescribed or sold
- MHRA approval (the marketing authorisation) always specifies the medicial conditions which the medicine has been approved for use, diseases for which human clinical trials have shown it to work, the use of medicines outside the MA conditions is considered "off-licence" and is common but may cause liability.
- MHRA also enforces medicines legislation by inspecting manufacturing facilities
- Monitors GLP, GMP, GCP and GPvP and gives mandatory guidelines for.
- Ensures patient information, leaflets, advertising etc meet the required standards. Monitors medicines throughout their lifetime from pharmacovigilence data such as the "yellow card" scheme.
- Works with the police and home office to detect, close down and prosecute illegal factories making counterfeits and unlicensed drugs.
National Institue for Health and Clinical Excellence (NICE)
- NICE is a department of the UK NHS
- Approves medicines for use in the NHS, and issues national guidance to promote good health and treatment and prevention of illness. Decisions and advice are evidence based.
- New medicines must be approved by NICE before they can be used/prescriped on the NHS (unless prescribed for an individual "named patient".
- Health technologies - evidence based guidance on use of new and existing treatment.
- Clinical Practice - evidence based guidance on appropriate treatment and care of people with conditions within NHS
- Public Health - evidence based guidance to NHS, local authorities and public sector workers on public health.